Understanding Migraine

Understanding Migraine
Maria Eliza Ruiz Aguila
A thesis submitted in fulfilment of the
requirements for the degree of
Doctor of Philosophy
Faculty of Health Sciences
The University of Sydney
2017
Candidate’s statement
I, Maria Eliza Ruiz Aguila, hereby declare that this submission is my own work and that it
contains no material previously published or written by another person except where
acknowledged in the text. Nor does it contain material which has been accepted for the award
of another degree.
I, Maria Eliza Ruiz Aguila, understand that if I am awarded a higher degree for mythesis
entitled “Understanding Migraine” being lodged herewith for examination, the thesis will be
lodged in The University of Sydney library and be available immediately for use. I agree that
the University Librarian (or in the case of a department, the Head of the Department) may
supply a photocopy or microform of the thesis to an individual for research or study or to a
library.
(Signed)
Maria Eliza Ruiz Aguila
31 March 2017
i
Supervisor’s statement
As primary supervisor of Maria Eliza Ruiz Aguila’s doctoral work, I certify that Iconsider
her thesis “Understanding Migraine” in fulfilment of the requirements for the degree of
Doctor of Philosophy (Health Sciences) is in a form ready for examination.
Primary Supervisor:
(Signed)
Dr Trudy Rebbeck
31 March 2017
ii
Acknowledgements
I am grateful to the people who contributed to the shaping and completion of this thesis.I
thank all my research supervisors for being admirable role models to me in research, teaching
and leadership. I thank my primary supervisor, Dr Trudy Rebbeck, and auxiliary supervisor,
Dr Andrew Leaver, for their hard work during and outside our weekly discussions. Their big-
picture thinking, balanced with their attention to details,facilitated the accomplishment of the
goals of our research project and empowered me to progress as a researcher, learner and
professional. Their perceptive ways opened many learning opportunities for me and nurtured
me beyond the requirements of the thesis. I also thank my auxiliary supervisors, Professor
Patrick Brennan, Professor Jim Lagopoulos, and Professor Kathryn Refshauge, for their
vision, scholarly guidance, and prompt and constructive feedback. Their expert advice and
encouragement were critical in making my candidature fulfilling.I thank my co-authors for
their significant contribution to the studies presented in this thesis. Their engagement and
insights taught me valuable lessons in collaborative research.
I thank the following important contributors to the studies: All the participants, for their time,
enthusiasm and commitment; the staff of the Southern Radiology Group at The University of
Sydney Brain and Mind Centre and the Sydney Specialist Physiotherapy Centre,for their
administrative and technical assistance; Dr Jillian Clarke, Mr Ray Patton and Mr Laurence
McCaul, for their technical assistance with equipment used in our studies; Headache
Australia, Australian Pain Society, Australian Pain Management Association, Painaustralia,
the editorial team of Ang Kalatas Australia, and Dr Craig Moore,for their help in recruiting
participants; and Professor Jenny Peat, for her advice on statistical analyses.
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I thank my colleagues and friends who rooted for me and celebrated my accomplishments,
big and small. I thank my colleagues in the Arthritis and Musculoskeletal Research Group for
providing an enabling environment. It was a privilege to be among achievers who were both
knowledgeable and supportive, who knew how to balance seriousness and fun, and whose
successes lifted my potential and morale.I thank the administration and staff of the University
of the Philippines College of Allied Medical Professions who,in my behalf, took care of
bureaucratic requirements related to my being on study leave. I thank the friends I met during
my candidature. They were limitlesssources of kindness, cheer, sanity, advice, and reality
checks. I thank them for being our family away from home. Their imprint on me will last for
life. I thank my long-time friends for keeping me grounded. They were my sounding boards
for ideas related to research and life.
I dedicate this thesis to my family. They have been my inspiration to always strive to be a
better person for others. Their confidence in me and emotional and spiritual support
strengthened my determination through the last four years.
Finally, I dedicate this thesis to my husband, Eric. Words cannot do justice to my gratitude
for him. His unconditional support and selflessness emboldened me to pursue this degree. His
willingness to take over tasks that should have been shared between us allowed me to
concentrate on and relish being a student researcher. His quiet strength was my source of
focus and calmness. I look forward to fulfilling the higher purpose of this experience with
him.
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Abstract
The aim of this thesis was to better characterise migraine through more detailed investigation
of selected headache-related factors and to compare these factors with those seen in other
commonly occurring recurrent headaches. The factors investigated in this thesis were
neurochemical profile; cervical musculoskeletal impairments; and patient experience,
represented by pain and disability characteristics, emotional state and other personal factors.
This thesis had six objectives: first, to describe how headaches are defined in clinical trials;
second, to compare levels of brain neurochemicals in migraine to controls; third, to explore
the relationship between brain neurochemicals and relevant disease characteristics of
migraine; fourth, to characterise cervical musculoskeletal impairments and patient experience
in migraine compared to non-migraine headaches and controls; fifth, to characterise the six-
month clinical course of migraine and non-migraine headaches and the factors associated
with the clinical course; and lastly, to examine changes in disability over six months in
migraine and non-migraine headaches.
To set the stage for characterising migraine and comparing it with non-migraine headaches
including tension-type headache (TTH) and cervicogenic headache (CGH), it was first
necessary to determine how these headaches were defined in clinical trials. Whilstthe
International Classification of Headache Disorders (ICHD) has been widely considered the
reference standard for classification and diagnosis of headaches, the extent of its application
in research wasunknown.In Chapter Two, a systematic review was conducted with the aim of
exploringand describingthe definitions of study populations in clinical trials of frequent
recurrent headaches including TTH, CGH and cluster headache. Data extracted from each
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study which defined the study population included the ICHD diagnostic criteria as reported in
theeligibility criteria and baseline characteristics of participants. This review
demonstratedthat there was general adherence (205 out of 229 studies, 89.5%) to the ICHD
criteria in defining study populations. However, whilst study populations were diagnosed
mostly through interview, clinical examination and diary entry, over half of all studies
(127/229, 55.5%) did not specify the method used to define the study population.
Furthermore, reporting of inclusion criteria differed between headache types: pain intensity
was most commonly reported for migraine and tension-type headache studies (n = 123,
66.1% and n = 21, 67.7%, respectively), episode frequency for cluster headache studies (n =
5, 71.4%), and neck-related pain for cervicogenic headache studies (n = 3, 60%). Few studies
described the extent to which study populations demonstrated ICHD features at baseline. The
findings of Chapter Two provide insight into applicability of results of clinical trials to
clinical populations and highlight the need for detailed reporting of participant selection in
research.
The levels of brain neurochemicals in migraine and the relationship between neurochemicals
and clinicalcharacteristics were explored ina case-control study (Chapters Three and Four).
Twenty individuals withmigraine and 20 age- and gender-matched controls were recruited. In
Chapter Three, the levels of neurochemicals, particularly gamma-aminobutyric acid (GABA),
were comparedbetween individuals with migraine and controls using proton magnetic
resonance spectroscopy (1H-MRS). Usingaspecialised technique called Mescher-Garwood
point resolved spectroscopy, two significantfindings were demonstrated. First, individuals
with migrainehad higher GABA levels[median (IQR)1.41 (1.31–1.50)institutional units]
compared to age- and gender-matched controls [1.18 (1.12–1.35)institutional units, p =
0.002]. Second, brain GABA levels hadgood diagnostic accuracy in classifying individuals as
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having migraine [area under the curve = 0.84 (95% confidence interval, CI, 0.71 to0.96), p<
0.001]. Specifically, brain GABA levels of 1.30 institutional units or higher had a positive
likelihood ratio of +2.67 to indicate migraine, with a sensitivity of 84.2% and specificity of
68.4%. These findings imply a putative role of GABA in the pathophysiology of migraine
and suggest the potential of GABA as a biomarker for migraine.
In Chapter Four, the process of validating GABA as a migraine biomarker was continued.In
this chapter,the association between brain GABA levels and clinical characteristics,including
pain, central sensitisation symptoms, emotional state, and headache-related disability, in
individuals with migraine were explored in a case-control design.Fair positive associations
were found between GABA levels and pain scores (ρ = .47, p = 0.04) and between GABA
levels and symptoms of central sensitisation (ρ = .48, p = 0.03). GABA levels were not
associated with headache history, frequency, duration or intensity, with symptoms of
emotional state, nor with levels of disability (p> 0.05).These findings corroborate the role of
GABA in migraine pathophysiology and its potential as a biomarker. These findings also
provide preliminary evidence for the usefulness of measuring pain and central sensitisation in
characterising migraine.
To characterise cervical musculoskeletal impairments and patient experience in different
headache types, we conducted a cross-sectional study in Chapter Five. The aim of this study
was to compare the prevalence and severity of these factors between migraine and non-
migraine headaches. Forty people with migraine, 45 people with non-migraine headaches
(TTH and CGH), and 40 controls participated. Fewer participants in the migraine group [n=4
(10%)] had cervical articular impairment compared to the non-migraine group [n=26 (58%);
p < 0.001].Further, migraine and non-migraine groups did not differ on cervical muscle
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impairment measures. Participants in the migraine group[median (IQR) 7.0 (6.0–7.0)]had
more intense pain (numerical rating scale 0–10)than non-migraine[5.0 (4.0–7.0)p = 0.009].
Similarly,the migraine group [43(31–53) out of 90]had higher disability scoreson Headache
Disability Questionnairethan the non-migraine group [27 (20–42); p = 0.006].Additionally, a
combination of the following variableshad 80.0% sensitivity and 75.6% specificity in
identifying migraine: no pain on manual examination of the cervical spine, less change in
deep cervical extensors thickness during contraction measured using real-time ultrasound
imaging, less frequent headaches, and higher disability scores. Thus Chapter Five presents
new evidence that a combination of tests can differentiate migraine from non-migraine
headaches.
In Chapter Six, we followed the same participants from the cross-sectional studyover 6
months in a longitudinal cohort design.The aim of this study was to characterisemigraine,
based on its clinical courseover 6 months. A secondary aim was to examine the extent to
which the clinical course was associated with demographic and headache characteristics,
cervical musculoskeletal impairments, and other personal factors.Participants underwent
physical examination of cervical musculoskeletal impairments at baseline, completed an
online diary daily for 6 months, and self-report questionnaires at baseline, 1, 3 and 6 months
after enrolment. Headache frequency, intensity and activity interference varied from month-
to-month for all headache types.However, day-to-day variability in headache intensity and
activity interference differed between migraine and non-migraine headaches, with greater
volatility demonstrated in migraine. A multifactorial model comprising migraine headache
group, receiving physical treatment, pain on manual examination of the upper cervical joints,
higher scores on disability questionnaires, and lower level of physical activity explained
27.7% of the variation in disability at 3 months (p = 0.040). Likewise, a multifactorial model
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comprising headache group, age, headache intensity, activity interference, pain on manual
examination of the upper cervical joints, disability scores and level of physical activity
explained 32.3 % of the variation in disability at 6 months (p = 0.031). Of these factors, pain
on manual examination of the upper cervical joints increased the odds of non-improvement in
disability by nearly 6 times [odds ratio (95% CI) = 5.58 (1.14 to 27.42); p = 0.034]. These
results therefore suggest that the clinical course of migraine is more volatile than non-
migraine headaches and that factorsinfluencing this clinical course include headache features,
cervical joint dysfunction, disability and physical activity.
The final objective of examining short- to medium-term changes in disability in different
headachetypes was investigated inChapter Seven.The internal responsiveness of four
commonlyused questionnaires was evaluated by calculating effect size, and external
responsiveness was calculated using receiver operating characteristic curve analysis.The
Headache Impact Test-6 and Headache Disability Questionnaire were the most responsive
questionnaires for individuals with both migraine and non-migraine headaches. At short-term
(3 months), effect sizes (84% CI) ranged from 0.31 (0.07 to 0.56) to 0.47 (0.11 to 0.82),
while at medium-term (6 months), effect sizes ranged from 0.40 (0.06 to 0.74) to 0.60 (0.26
to 0.94). Headache Disability Questionnaire generally had the greatest external
responsiveness to change in headache frequency at both short- and medium-term [areas under
the curve (95% CI) 0.52 (0.32 to0.72) to 0.69 (0.49 to 0.89). These findings add to the
evidence presented in Chapter Four by demonstrating that the HIT 6 and the HDQ are
usefulquestionnaires to use in clinical practice.
Collectively, this thesis provides deeperinformation regardingthe nature and characteristics of
migraine compared with non-migraine headaches, including TTH and CGH.This thesis has
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established the potential of GABA as a biomarker for migraine, and thus implies the possible
role of GABA in the disease process. In addition to exploring the neurochemical profile, this
thesis has also characterised migraine according to cervical musculoskeletal impairments and
patient experience embodying disability, pain, central sensitisation, and other personal
factors. The implications for clinical practice are to assess cervical musculoskeletal
impairments and patient experience to facilitate diagnosis and prognostication, and to educate
patients on the nature of their headaches. Findings from the thesis may also be used by
guideline developers, providing stimulus for further discussions regarding the definition of
migraine and the reporting of participant selection criteria, with reference to this definition, in
clinical trials. Future research directions are identified in validating GABA as a biomarker for
migraine and elucidating its pathophysiology. By characterising migraine more fully, findings
from this thesis will inform the development of effective treatments that possibly could be
targeted at GABA or at the clinical characteristics found to be present in migraine. Ultimately
this should achieve better health outcomes for people with migraine and other headaches.
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Table of contents
Candidate’s statement ............................................................................................................ i
Supervisors’statement .......................................................................................................... ii
Acknowledgements .............................................................................................................. iii
Abstract ................................................................................................................................ v
Table of contents .................................................................................................................. xi
Thesis structure ................................................................................................................. xvii
Publications, presentations and prizes ............................................................................... xviii
CHAPTER ONE Current understanding of migraine and recurrent non-migraine neck-
related headaches ................................................................................................................ 1
Headache definition, classification and diagnosis ............................................................ 4
The prevalence of migraine and non-migraine headaches .............................................. 11
The burden of migraine and non-migraine headaches .................................................... 12
Clinical presentation and course of migraine and non-migraine headaches .................... 14
Clinical presentation ................................................................................................ 15
Overlaps and variability in clinical presentation ....................................................... 18
Clinical course ......................................................................................................... 20
Cervical musculoskeletal impairments in migraine and non-migraine headaches ........... 23
Rationale for considering cervical musculoskeletal impairments .............................. 23
Neck pain ................................................................................................................ 24
Cervical articular impairments ................................................................................. 24
Cervical muscle impairments ................................................................................... 26
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Overview of pathophysiology of migraine and non-migraine headaches ........................ 29
Common anatomy and physiology of headaches ...................................................... 29
Overview of pathophysiology of migraine ............................................................... 34
Overview of pathophysiology of a non-migraine headache:Tension-type headache .. 38
Overview of pathophysiology of a non-migraine headache: Cervicogenic headache 39
Alternative hypothesis on shared pathophysiology of migraine and TTH: Continuum
theory ................................................................................................................ 40
Gaps in evidence on pathophysiology addressed in this thesis .................................. 42
Assessment to characterise migraine and non-migraine headaches ................................. 43
Interview ................................................................................................................. 43
Headache diary ........................................................................................................ 44
Physical examination tests for cervical musculoskeletal impairments ....................... 44
Self-report questionnaires ........................................................................................ 45
Assessment of migraine and non-migraine headaches used in this thesis .................. 46
Recognising factors that influence the patient experience in headaches .......................... 47
The importance of assessing more than the diagnostic criteria.................................. 47
Factors influencing the patient experience ............................................................... 47
Biomedical and personal factors assessed in this thesis ............................................ 50
Summary ....................................................................................................................... 51
Aims of the thesis .......................................................................................................... 52
References ..................................................................................................................... 53
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CHAPTER TWO Definitions and participant characteristics of frequent recurrent
headaches........................................................................................................................... 67
Authorship statement ..................................................................................................... 68
Abstract ......................................................................................................................... 70
Introduction ................................................................................................................... 71
Methods ........................................................................................................................ 73
Results .......................................................................................................................... 75
Discussion ..................................................................................................................... 77
Conclusions ................................................................................................................... 79
Article highlights ........................................................................................................... 81
References ..................................................................................................................... 82
Figures .......................................................................................................................... 86
Tables ........................................................................................................................... 88
CHAPTER THREE Elevated levels of GABA+ in migraine detected using proton
magnetic resonance spectroscopy ..................................................................................... 92
Authorship statement ..................................................................................................... 93
Abstract ......................................................................................................................... 95
Introduction ................................................................................................................... 97
Methods ........................................................................................................................ 99
Results ........................................................................................................................ 104
Discussion ................................................................................................................... 105
Conclusions ................................................................................................................. 108
References ................................................................................................................... 110
Tables ......................................................................................................................... 116
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Figures ........................................................................................................................ 118
CHAPTER FOUR The association between clinical characteristics of migraine and
brain GABA levels .......................................................................................................... 124
Authorship statement ................................................................................................... 125
Abstract ....................................................................................................................... 128
Introduction ................................................................................................................. 130
Methods ...................................................................................................................... 132
Results ........................................................................................................................ 136
Discussion ................................................................................................................... 138
Conclusions ................................................................................................................. 142
References ................................................................................................................... 144
Figures ........................................................................................................................ 154
Tables ......................................................................................................................... 159
Highlights ................................................................................................................... 162
CHAPTER FIVE Characterizing cervical musculoskeletal impairments and patient
experience in migraine as distinguished from non-migraine headaches ....................... 163
Abstract ....................................................................................................................... 167
Introduction ................................................................................................................. 169
Methods ...................................................................................................................... 171
Results ........................................................................................................................ 176
Discussion ................................................................................................................... 185
Conclusions ................................................................................................................. 188
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References ................................................................................................................... 191
Figure .......................................................................................................................... 198
CHAPTER SIX Six-month clinical course and predictors of factors associated with non-
recovery of migraine and non-migraine headaches ....................................................... 199
Abstract ....................................................................................................................... 203
Introduction ................................................................................................................. 205
Methods ...................................................................................................................... 206
Results ........................................................................................................................ 210
Discussion ................................................................................................................... 214
Conclusions ................................................................................................................. 217
Clinical implications.................................................................................................... 219
References ................................................................................................................... 220
Figures ........................................................................................................................ 227
Tables ......................................................................................................................... 233
CHAPTER SEVEN Responsiveness of disabilityquestionnaires in migraine and non-
migraine headaches ......................................................................................................... 238
Abstract ....................................................................................................................... 241
Introduction ................................................................................................................. 243
Methods ...................................................................................................................... 245
Results ........................................................................................................................ 248
Discussion ................................................................................................................... 250
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Conclusions ................................................................................................................. 253
References ................................................................................................................... 255
Tables ......................................................................................................................... 259
CHAPTER EIGHT Conclusion ...................................................................................... 264
Overview of findings ................................................................................................... 265
Implications of the thesis ............................................................................................. 267
Headache definitions ............................................................................................. 267
Clinical practice ..................................................................................................... 268
Limitations of the thesis ......................................................................................... 274
Directions for future research................................................................................. 275
References ................................................................................................................... 280
APPENDICES ................................................................................................................. 284
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Thesis structure
This thesis is structured as a thesis by publication, comprising chapters that can be read
independently. The University of Sydney accepts papers that have been published, accepted
for publication or submitted for publication written during the candidature to be included in
the thesis. Thus Chapters Two, Three and Four are presented in their versions accepted for
publication in refereed journals. Links to the publisher’s versions are provided on the title
pages of these chapters. Chapter Six is presented in its peer reviewed version accepted for
publication with revisions. Chapters Five and Seven are presented in the format following
guidelines of the refereed journals to which they were submitted for publication. Because
Chapters Two to Seven appear in journal publication format, each of these chapters contains
its own abstract, introduction, methods, results, discussion, conclusion, and reference list.
Similarly, Chapters One and Eight each has its own reference list. Appendices for specific
chapters appear at the end of the thesis.
The aims of this thesis can be found in the abstract, Chapter One and Chapter Eight. Chapter
One serves as the introductory chapter for the thesis and therefore presents concepts related to
Chapters Two to Seven. Chapter Eight serves as the concluding chapter and summarises the
findings and their implications to headache definitions, clinical practice and future research.
The studies presented in Chapters Two to Seven were granted ethics approval by The
University of Sydney Human Research Ethics Committee.
Please note that the table of contents is interactive. Click on either words or the page number
to jump to a particular section.
xvii
Publications, research dissemination and awards
Parts of the work presented in this thesis have been published and /or presented.
Published peer-reviewed papers
Aguila ME, Rebbeck T, Mendoza KG, De La Peña MG, Leaver AM. Definitions and
participant characteristics of frequent recurrent headache types in clinical trials: A
systematic review. Cephalalgia. Epub 2017 Apr 25. doi: 10.1177/0333102417706974
Aguila ME, Rebbeck T, Leaver AM, Lagopoulos J, Brennan PC, Hübscher M, ,Refshauge
KM. The association between clinical characteristics of migraine and brain GABA
levels: An exploratory study. J Pain. 2016; 17:1058–67.
doi:10.1016/j.jpain.2016.06.008
Aguila ME, Lagopoulos J, Leaver AM, Rebbeck T, Hübscher M, Brennan PC, Refshauge
KM. Elevated levels of GABA+ in migraine detected using 1H-MRS. NMR Biomed.
2015; 28:890–7. doi: 10.1002/nbm.3321
Paper accepted for publication
Aguila ME, Rebbeck T, Hau SA, Ali K, Pope A, Ng K, Leaver AM. Six-month clinical
course and factors associated with non-improvement in migraine and non-migraine
headaches. Cephalalgia (accepted with revision).
xviii
Papers submitted for publication
Aguila ME, Leaver AM, Hau SA, Ali K, Ng K, Rebbeck T. Characterizing cervical
musculoskeletal impairments and patient experience in migraine as distinguished
from non-migraine headaches. J Headache Pain (submitted).
Aguila ME, Leaver AM, Ng K, Rebbeck T. Responsiveness of disability questionnaires in
migraine and non-migraine headaches. Qual Life Res (submitted).
Published abstracts / Conference proceedings
Aguila ME, Rebbeck T, Leaver AM, Lagopoulos J, Brennan PC, Hübscher M, Refshauge
KM. Pain and self-reported central sensitisation symptoms are associated with brain
gamma-aminobutyric levels in migraine: Insights for physiotherapy assessment.
Conference abstract e-book of Connect Physiotherapy Conference 2015: Australian
Physiotherapy Association Conference 2015; 2015 Oct 3–6; Gold Coast, QLD
(Australia). p. 3.
Aguila ME, Leaver A, Rebbeck T, Lagopoulos J, Brennan P, Hübscher M, Refshauge K.
Clinical characteristics associated with perceived disability and GABA level in adults
with migraine: Insights for physiotherapy assessment [abstract].
Physiotherapy.(Special Issue for World Confederation for Physical Therapy Congress
2015) 2015;101:e37–8.
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Aguila ME, Lagopoulos J, Leaver AM, Rebbeck T, Hübscher M, Brennan PC, Refshauge
KM. Elevated GABA level in occipital region in migraine detected using proton
magnetic resonance spectroscopy. Conference handbook of the Australian Pain
Society 34th Annual Scientific Meeting; 2014 Apr 13–16; Hobart, TAS (Australia).
p. 77.
Conference presentations: Podium
Distinguishing migraine from non-migraine headaches based on pain, disability and neck
impairments. 2017 Australian Pain Society 37th Annual Scientific Meeting. 9–12
April 2017, Adelaide, SA, Australia.
Pain and self-reported central sensitisation symptoms are associated with brain gamma-
aminobutyric levels in migraine: Insights for physiotherapy assessment. Australian
Physiotherapy Association Conference 2015. 3–6 October 2015, Gold Coast, QLD,
Australia.
Clinical characteristics associated with GABA level in adults with migraine: What’s next?
Masterclass Symposium 2015 (organised by the Australian Specialist Physiotherapy
Education). 1 August 2015, Sydney, NSW, Australia.
Clinical characteristics associated with perceived disability and GABA level in adults with
migraine: Insights for physiotherapy assessment. WCPT Congress. 1–4 May 2015,
Singapore.
xx
Exploratory study of the association between clinical characteristics of migraine and levels
of gamma-aminobutyric acid. FHS Biennial HDR Conference (Imag!ne.U – Creating
the Future). 3–5 November 2014, Sydney, NSW, Australia.
Understanding migraine using proton magnetic resonance spectroscopy. APA Symposium
ACT 2014 Research Symposium. 23 August 2014, Canberra, ACT, Australia.
Elevated GABA level in occipital region in migraine detected using proton magnetic
resonance spectroscopy. Australian Pain Society's 34th Annual Scientific Meeting.
13–16 April 2014, Hobart, TAS, Australia.
Can neurochemicals distinguish headache types? Masterclass Symposium 2013 organised by
the Australian Specialist Physiotherapy Education. 29 June, 2013, Sydney, NSW,
Australia.
Conference presentations: Poster
Levels of GABA in the brain have good diagnostic accuracy for migraine. SPR:ING (Sydney
Pain Researchers: Introducing the Next Generation) 2015 Symposium, 15 December
2015, Sydney, NSW, Australia.
Occipital concentration of GABA has good diagnostic accuracy for migraine. 15th World
Congress on Pain. 6–11 October 2014, Buenos Aires, Argentina.
xxi
Other forms of research dissemination
• Media spokesperson for the study on GABA levels in migraine (Chapter Three in this
thesis). The study was released to the media in October 2015, gaining an estimated
audience reach of more than 2 million people, with the biggest audience share from
television. A summary from The University of Sydney media office can be found in
Appendix 6.
• Cover art for The Journal of Pain Volume 17, Issue 10 (October 2016)
(http://www.jpain.org/issue/S1526-5900(16)X0011-9). The cover illustration. The cover
illustration was a stylised image from an output of the editing process of GABA from the
study in Chapter Four published in the same issue: [Aguila ME, Rebbeck T, Leaver AM,
Lagopoulos J, Brennan PC, Hübscher M,Refshauge KM. The association between clinical
characteristics of migraine and brain GABA levels: An exploratory study. J Pain. 2016;
17:1058–67.doi:10.1016/j.jpain.2016.06.008]. A copy of the cover art can be found in
Appendix 7.
Invited presentations
The role of GABA in primary headaches. Primary headache in our hands: A bottom up
perspective (a symposium organised by the Watson Headache Institute), 30–31 July
2016, Sydney, NSW, Australia.
How to create an online survey using Research Electronic Data Capture (REDCap).
Workshop facilitated at The University of Sydney Faculty of Health Sciences, 17
March 2016, Sydney, NSW, Australia.
xxii
How to create an online survey using Research Electronic Data Capture (REDCap).
Workshop facilitated during the HDR Bazaar at The University of Sydney Faculty of
Health Sciences, 2 November 2015. Sydney, NSW, Australia.
What is a clinically worthwhile treatment effect? Workshop facilitated during the Philippine
Physical Therapy Association-University of Sydney Collaboration Continuing
Professional Development Activity. 29 August 2015, Manila, Philippines.
Role of physical therapy in headache management. Philippine Physical Therapy Association-
University of Sydney Collaboration Continuing Professional Development Activity.
29 August 2015, Manila, Philippines.
Using Research Electronic Data Capture (REDCap) as a data management tool: What, why,
how. Workshop at The University of Sydney Faculty of Health Sciences, 22 July
2015. Sydney, NSW, Australia.
Awards and grants
The candidate received the following awards and grants during her candidature:
• University of Sydney International Scholarship
• UP Research Dissemination Grant awarded by the University of the Philippines to
present at the Australian Physiotherapy Association Conference 2015 in Gold Coast,
QLD, Australia, 3–6 October 2015
• IASP Financial Aid Award conferred by the International Association for the Study of
Pain to attend the 15th World Congress on Pain in Buenos Aires, Argentina, 6–11
October 2014
xxiii
• Finalist, University of Sydney 3-Minute Thesis Competition, Sydney, Australia, 20
August 2014
• Winner, Three-Minute Thesis Competition, Faculty of Health Sciences, (Faculty of
Health Sciences Dean’s Research Scholar Award) The University of Sydney, Sydney,
Australia, 26 June 2014
• PhD Student Travel Grant awarded by the Australian Pain Society to attend its 34th
Annual Scientific Meeting held in Hobart, TAS from 13–16 April 2014
Other grants received
• Member of HDR Student Executive Group awarded a Healthy Sydney University
student scholarship for 2017 to implement HDR Student Stepathon, aimed to support
student-led initiatives, such as the, to promote wellbeing
• Member of HDR Student Executive Group awarded an HDR+ Students Grant for
2015 to implement the HDR Bazaar, aimed to enhance the academic experience and
outcomes of higher degree by research programs
• Member of the team awarded a Sydney Southeast Asia Centre Research Capacity
Building Grant in 2015 aimed to improve productivity in clinical rehabilitation
research through partnerships between Australia and the Philippines
Additional work by the author not forming part of this thesis
Trott, CA, Aguila, MER, Leaver, AM. The clinical significance of immediate symptom
responses to manual therapy treatment for neck pain: Observational secondary data
analysis of a randomized trial. Man Ther. 2014;19:549–54.doi:
10.1016/j.math.2014.05.011
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CHAPTER ONE
Current Understanding of Migraine and
Recurrent Non-Migraine Neck-Related Headaches
1
This is Meg. She’s that girl who makes plans with friends
then cancels at the last minute, giving the migraine excuse.
“Migraine Meggy”, she’d be teased, but then her friends
realised it really wasn’t funny!

Illustration by David Val Christian B. Agoncillo, 2014
forpresentations related to studies in this thesis
Meg’s friends thought that migraine was just a bad headache; but it’s more
than that. Sure, Meg gets headaches –severe, throbbing headaches that are
unrelenting for a day or two each time. But aside from headaches, Meg’s
migraines make her vomit and intolerant to light, so much so that she had to
install block out curtains. During her migraine attacks, Meg lies still in her
dark room, debilitated and frustrated, waiting for her symptoms to pass or for
science to find a cure.
[Excerpt from Three-Minute Thesis Presentation (3MT®) by Maria Eliza Ruiz Aguila;
Winner,Faculty of Health Sciences 3MT® 2014]
The more we know about characteristics of frequently occurring headaches, the more Meg
and her friends might understand these conditions. With better understanding, we might also
move closer to effective targeted headache treatments. Thus the aim of this thesis was to
further characterise migraine and other headaches that most frequently present in primary
care namely tension type headache and cervicogenic headache. This was achieved by firstly
exploring conventions in classification and diagnosis. The next step was an exploration of the
neurochemical profile of migraine, which yielded new findings about migraine biochemistry.
The final step was to investigate cervical musculoskeletal impairments, clinical
characteristics and elements of a patient’s experience that characterise migraine and
distinguish it from other headache types.
2
This introductory chapter provides a background on the current understanding of migraine
and other frequently presenting recurrent headaches. In the first section, headaches, in
general, and migraine, tension-type headache and cervicogenic headache, in particular, are
defined according to the most accepted classification system, the International Classification
of Headache Disorders. These definitions directly influence prevalence estimates of these
recurrent neck-related headaches. Therefore the next section discusses the prevalence and
associated burden of these headaches. Next, an overview of the clinical features and course of
these headaches is discussed, followed by a depiction of cervical musculoskeletal
impairments which may be common to migraine, tension-type headache and cervicogenic
headache. Pathophysiologic mechanisms which may relate with the clinical features and
course of migraine, tension-type headache and cervicogenic headache are then briefly
described. This section on pathophysiology also includes a summary of extant evidence on
neurochemical profile in migraine. The current understanding of the clinical features and
pathophysiology of these recurrent headaches directly influences their assessment. Therefore
the previous sections set the stage for the subsequent section on assessment of these
headaches. To broaden the perspective on the pain experience of patients with migraine,
tension-type headache and cervicogenic headache, a section is provided describing factors
that may influence patient experience, and the importance of measuring these factors and the
impact of headache on patients’ lives.
3
Current understanding of migraine and recurrent non-migraine neck-
related headaches
1.1. Headache definition, classification and diagnosis
The term “headache” refers to a symptom of many disorders and is characterised as either a
painful or nonpainful discomfort of the entire head, including the face and upper neck (1).
“Headache” may also refer to an independent disorder characterised by headache and other
associated symptoms. Because the term “headache” may be used inconsistently, a consensus
on headache terminology is necessary to facilitate communication in research and clinical
practice.
The first demonstration of a consensus in headache terminology was with the publication of a
classification system for headache disorders in 1962 (1). This classification system was based
on aetiology of headaches and comprised brief definitions of a limited number of headache
types. Headaches were then classified as “vascular headache” or “muscle-contraction”
headache, and so forth. This system eventually was perceived to be inadequate and confusing
(2). Headache practitioners acknowledged the need for a better classification system that
would operationally define headache types. Thus the International Classification of Headache
Disorders (ICHD) emerged (3). ICHD was the first classification system to be accepted
internationally as the uniform approach to the classification and diagnosis of headache
disorders in clinical practice and research (4). The operational definitions in ICHD
wereoriginally based on clinical descriptions of headache attacks and mostly based on expert
opinion, in the absence of published evidence at that time. Increased evidence from clinical
4
trials and longitudinal and epidemiological studies of, genetics, neuroimaging, and
pathophysiology from have since contributed to the evolution of ICHD.
The ICHD, now its third edition, beta version (ICHD-3 beta),is the reference standard for
headache classification and diagnosis (5, 6). ICHD reflects research evidence on which
headache types should be classified, which rules to apply to diagnose the headache types, and
how to organise these headache types. The current ICHD divides headaches into three
groups; primary headache, secondary headache and other headaches not better classified as
primary or secondary headache. This third group includes painful cranial neuropathies and
other facial pain. Across the three parts of ICHD are 14 main headache types, each defined
operationally with key clinical criteria required for its diagnosis. Primary headaches are those
whose aetiologies are unknown and which exist independent from any other medical
condition (7), such as migraine, tension-type headache (TTH) and cluster headache. In
contrast, secondary headaches are those whose aetiologies are known, attributed to another
medical disorder, such as headaches due to trauma, vascular disorder, infection, and disorder
of the neck (such as cervicogenic headache, CGH). Thus primary headaches, like migraine
and TTH, are classified and diagnosed based on headache features whilst secondary
headaches, such as CGH are classified and diagnosed based on headache features, the
presence of the causative disorder and evidence for causation of the headache by the
causative disorder (8).
Definitions for migraine and non-migraine headaches, such as TTH and CGH, have been
refined over the three editions of the ICHD. Whilst the diagnostic criteria for these headaches
have not fundamentally changed from the first to the third editions of ICHD, these criteria
5
have been revised to reflect current evidence and to improve applicability of the criteria (9).
The current diagnostic criteria for migraine, TTH and CGH are presented in Table 1.
The diagnostic criteria in Table 1 specifying the minimum number of attacks or episodes for
classification of migraine, TTH and CGH connote the recurrent nature of these headaches.
The diagnostic criteria also illustrate how TTH and CGH are relatively “featureless”
compared to migraine, as many of the diagnostic features of TTH and CGH refer to absence
of symptoms (10).
Compared to the clear definitions of migraine and TTH since the first ICHD, it was only
since the second ICHD that CGH has been recognised as a discrete headache. Prior to this,
ICHD referred to “headache…associated with disorder of …neck…” (3). This was despite
the introduction of the term “cervicogenic headache” by Sjaastad and colleagues in 1983 (11)
to refer to headaches provoked by head or neck movements. The non-use of the term
“cervicogenic headache” as a headache classification in the first ICHD reflected the view that
CGH was not considered sufficiently proven in the absence of a neck disorder (12). Aside
from the ICHD definition, an even more specific definition of CGH is provided by the
Cervicogenic Headache International Study Group (CHISG) (13). A comparison between the
ICHD and the CHISG definitions of CGH is presented in Table 2. The required criteria for
diagnosis differ between the two classification systems. For example, ICHD required clinical
evidence of cervical lesion whilst the CHISG required diagnostic blockade. The CHISG
criteria also lists other characteristics of less importance for diagnosis which are not included
in the ICHD criteria.
6
Table 1. Diagnostic criteria for migraine, tension-type headache and cervicogenic headache
The International Classification of Headache Disorders, 3rd edition (beta version) Infrequent episodic tension-type headache
Cephalalgia. 2013;33:629–-808. Headache lasting from 30 minutes to 7 days
Headache has at least two of the following characteristics
• Bilateral location
Migraine without aura • Pressing or tightening (non-pulsating) quality
Headache attacks lasting 4–72 hours (untreated or unsuccessfully treated) • Mild or moderate intensity
Headache has at least two of the following characteristics: • Not aggravated by routine physical activity such as walking or climbing stairs
• Unilateral location Both of the following:
• Pulsating quality • No nausea or vomiting
• Moderate or severe pain intensity • No more than one of photophobia or phonophobia
• Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing At least 10 episodes fulfilling the above criteria
stairs)
During headache at least one of the following Frequent episodic tension-type headache
• Nausea and/or vomiting Similar criteria as infrequent episodic tension-type headache except
• Photophobia and phonophobia At least 10 episodes of headache occurring on 1–14 days per month on average for >3 months (≥ 12
At least 5 attacks fulfilling the above criteria and <180 days per year)
Migraine with aura Chronic tension-type headache

Aura consisting of at least one of the following fully reversible aura symptoms: Similar criteria as episodic tension-type headache except
• Visual Headache occurring on ≥15 days per month on average for >3 months (≥180 days per year)
• Speech and/or language
• Motor Cervicogenic headache
• Brainstem Clinical, laboratory and/or imaging evidence of a disorder or lesion within the cervical spine or soft
• Retinal tissues of the neck known to be able to cause of headache
At least two of the following: Evidence of causation demonstrated by at least two of the following:
• At least one aura symptom spreads gradually over ≥ 5minutes, and/or two or more • Headache has developed in temporal relation to the onset of the cervical disorder or
symptoms occur in succession appearance of the lesion
• Each aura symptom lasts 5–60 minutes • Headache has significantly improved or resolved in parallel with improvement in or
• The aura is accompanied, or followed within 60 minutes, by headache resolution of the cervical disorder or lesion
At least 2 attacks fulfilling the above criteria • Cervical range of motion is reduced and headache is made significantly worse by
provocative manoeuvres
• Headache is abolished following diagnostic blockade of cervical structure or its nerve
supply
7
Table 2. Comparison of diagnostic criteria for cervicogenic headache
The International Classification of Headache Diagnostic Criteria Cervicogenic Headache International

Disorders, 3rd edition (beta version) Study Group
Cephalalgia. 2013;33:629–808. Headache. 1998;38(6):442–445.
Required criterion: Clinical, laboratory and/or imaging Clinical, laboratory and/or
evidence of a disorder or lesion within the cervical imaging evidence of a
spine or soft tissues of the neck known to be able cervical lesion
to cause of headache
At least two of the following: Evidence of causation of At least one of the following (in decreasing
• Headache has developed in temporal the headache by the importance) :
relation to the onset of the cervical disorder cervical spine lesion • Headache pain similar to the usually
or appearance of the lesion occurring one induced subjectively
• Headache has significantly improved or and/or iatrogenically (part of
resolved in parallel with improvement in or confirmatory combination of criteria)
resolution of the cervical disorder or lesion o by neck movement and/or
• Cervical range of motion is reduced and sustained awkward head
headache is made significantly worse by positioning,(may be the
provocative manoeuvres sole criterion for neck
involvement), and/or
• Headache is abolished following diagnostic
blockade of cervical structure or its nerve o by external pressure over
supply the upper cervical or
occipital region on the
symptomatic side
• Restriction of cervical range of motion
• Ipsilateral neck, shoulder, or arm pain
of a rather vague non-radicular nature
or, occasionally, arm pain of a
radicular nature
Evidence by diagnostic anaesthetic blockades
(part of confirmatory combination of criteria)
Unilaterality of the head Part of confirmatory combination of criteria for

pain, without sideshift scientific work
Other characteristics that Moderate-severe, non-throbbing, and non-

are not part of lancinating pain, usually starting in the neck
confirmatory combination Episodes of varying duration
of criteria Fluctuation, continuous pain
Only marginal effect or lack of effect of
indomethacin
Only marginal effect or lack of effect of
ergotamine and sumatriptan
Female sex
Not infrequent occurrence of head or indirect
neck trauma by history, usually of more than
only medium severity
Various attack-related phenomena, only
occasionally present, and/or moderately
expressed when present
• Nausea
• Phonophobia and photophobia
• Dizziness
• Ipsilateral “blurred vision”
• Difficulties on swallowing
• Ipsilateral oedema, mostly in the
periocular area
8
For purposes of this thesis, study populations for migraine and non-migraine headaches (TTH
and CGH) were defined using the ICHD diagnostic criteria. For CGH, ICHD was used
instead of CHISG criteria for consistency with the other headache types, as ICHD lists
criteria for migraine, TTH and CGH. We also could not fulfil CHISG criteria in our protocols
because we did not include diagnostic blockade, which is required to confirm diagnosis using
CHISG criteria.
Efforts continue toward further improving the ICHD to mirror the advancing state of
evidence on headaches. Thus far, the ICHD has been a useful tool in understanding
headaches and in developing and evaluating new headache treatments. The ICHD has been
deemed useful to clinicians when a patient’s diagnosis is uncertain, and to researchers, in
selecting patients for clinical trials (4). Being internationally accepted, the ICHD represents
agreement among headache practitioners in headache classification. As such, ICHD
facilitates the conduct of epidemiological studies on the prevalence and disability rates of
certain headache types. Consequently ICHD contributes to the appreciation of headaches as a
public health concern.
Despite continuous efforts to improve the classification system, there remain challenges in its
use related to the nature of the classification system itself and the nature of the headaches.
First, diagnosis based on headache features as in ICHD may be challenging because
symptoms may overlap between headache types (14). Further one headache type may coexist
with one or more other headache types (15) which may influence the ability to detect a
headache diagnosis (16). Symptom overlap or coexistence of other headaches may be the
reason for at least 50% of migraine cases being misdiagnosed as other headache types, such
as episodic tension-type headache (17), sinus headache or stress-related headache (18).
9
Second, the decision rules in the ICHD present diagnostic criteria for each headache types
as a combination of clinical features. For example, diagnosis for migraine without aura
requires that two criteria be met, at least two of four symptoms for one criterion be present,
and at least one of two symptoms in another criterion be present (see Table 1) (8). These
decision rules increase the sensitivity of the ICHD but also increases the heterogeneity of
the possible clinical presentations of a particular headache diagnosis. Another criticism for
such a system is its complexity may be confusing and consequently influence reliability of
diagnosis (19).
Despite these challenges in headache diagnosis, the ICHD remains the most widely
accepted classification system for headache diagnosis. In fact, guidelines for clinical trials
of headaches recommend using the ICHD in selecting participants such that all participants
fulfil the diagnostic criteria for the headache being studied (20-22). Such guidelines allow
standardisation of study populations despite the complex presentations of headaches. In the
clinics, however, the extent of use of ICHD for diagnosis is unknown. This may be
interesting to know as the ICHD is not designed to be used for day-to-day clinical practice
for obvious headache cases but only when the diagnosis is uncertain (8).Chapter Two presents
the extent of application of ICHD in defining study populations in treatment efficacy trials.
Diagnosis could be improved by a better understanding of mechanisms, especially of the
primary headaches. Elucidating pathophysiological mechanisms of migraine and TTH, for
example, could add objective criteria to the classification system. These could include
biological markers, presented in ChaptersThree and Four,for migraine. As well, other
clinical features beyond those currently listed in the ICHD diagnostic criteria could be
explored to improve diagnosis and improve understanding of headaches. Thus we compared
clinical features between headache groups in Chapters Five and Six. 10

1.2. The prevalence of migraine and non-migraine headaches
Headaches are among the most prevalent disorders in the world. Prevalence studies estimate
that half to three quarters of adults aged 18 to 65 years in the world have had a headache in
the last year (23), with about half (47%) having an active headache disorder (24).Three of the
most prevalent headaches are migraine and non-migraine headaches, namely TTH and
CGH. Of these three, migraine and TTH are the most prevalent, affecting more than 10% of
the world population (25). It is therefore not surprising that migraine, TTH and the
combination of these are the top three headaches seen in primary and specialist clinics (23).
Migraine ranks seventh in global prevalence among all disorders according to the 2013
Global Burden of Disease Study, affecting nearly 850 million individuals (25). Among
headaches, migraine ranks second, with a total prevalence of 10%, and 11% among adults
(24). Females are two to three times as likely as males to have migraine (14). Thus the
prevalence of migraine among adults is different between females (mean = 16.6%) and males
(mean = 7.5%) (26). The most common age of onset of migraine is between 20 to 30 years
(27). Its prevalence increases with age, peaks at around 40 years, after which the prevalence
declines, especially for women (14).
TTH is more prevalent than migraine, ranking second among all disorders according to the
2013 Global Burden of Disease Study, affecting about 1.6 billion individuals (25). Unlike
migraine, females are only slightly more affected by TTH than males, with a male:female
ratio of 4:5 (14). Thus the prevalence of TTH among adults is also only slightly different
between females (mean = 22.36%) and males (mean = 16.9%). (26) Compared to migraine,
11
TTH has a later age of onset between 25 and 30 years (14). Its prevalence peaks between 30
and 39, increases until 50 years, and slightly declines with age.
The third most prevalent headache seen in primary and specialist care is CGH (28).
Compared to the epidemiological studies for migraine and TTH, only a few have investigated
CGH. Of the few prevalence studies on CGH, most were clinic-based studies that calculated
prevalence rates of CGH as defined by ICHD or the CHISG, resulting in varied prevalence
estimates. In a small study using modified ICHD criteria, prevalence of CGH was estimated at
17.8% among adults with frequent headaches aged 20 to 59 years (29). Another clinic-based
study among adults with idiopathic headaches (30) that used ICHD criteria (3) reported CGH
prevalence to be 16.1%. Larger studies resulted in smaller prevalence estimates. For example,
prevalence was estimated by Sjaastad and colleagues (31) to be 4.1% for adults aged 18 to 65
years old fulfilling the CHISG criteria (32). In the only population study of CGH prevalence
to date [(33) cited in (34)], even lower prevalence estimates were reported: 0.4% using the
ICHD criteria (3) and 1% applying five criteria of the CHISG (32). The varied prevalence
estimates for CGH nevertheless indicates that CGH is among the most frequently seen
headaches in the clinics.
1.3. The burden of migraine and non-migraine headaches
Headaches cause substantial burden on the individual and the society. On the individual level,
burden arises from the pain and other symptoms associated with the headache (35). These
symptoms may reduce functional ability, which may, in turn, reduce work productivity and
pay. Work loss for individuals with headaches is estimated at 4.2 days per year, with 70% of
12
this time lost due to reduced effectiveness at work (36). This cost of headaches on work
productivity and income is highlighted because headaches are more prevalent in the work
productive years. For individuals with recurrent headaches, the burden caused by the
headache is not only present when symptoms are active but also in between headache
episodes. Individuals with headaches may need to modify their lifestyle and defer social
activities in attempt to prevent another headache episode.
On the societal level, burden arises from direct treatment costs and the indirect costs of
reduced work productivity. Between direct and indirect costs, direct costs are estimated to be
lower because 50% of individuals with headaches worldwide do not consult health
professionals (23), Therefore the burden of headaches is believed to be underestimated (14).
Nevertheless, the burden due to the two most prevalent headaches, migraine and TTH, has
been characterised in a number of population studies.
Migraine is the sixth most disabling condition in the world in 2013, making it the most
disabling headache, based on years lived with disability (YLDs) (25). Disability calculated
using YLDs considers prevalence and severity of health loss. Migraine is more disabling than
TTH based on YLDs, causing more than 28 billion YLDs, compared to more than 2 million
YLDs for TTH (25). A slightly different picture is presented when disability is calculated
using frequency, duration of headache episode and intensity. Using this calculation, TTH
was found to cause disability at least as much as, if not more than, as migraine (24). It is
apparent then that migraine and TTH are the two most disabling headaches, migraine for its
higher severity than TTH, and TTH, for its higher prevalence than migraine.
13
No epidemiologic study has focused on disability due to CGH. Yet evidence from clinic-
based studies and randomised controlled trials indicates that individuals with CGH
experience disability comparable with that in migraine and TTH. In a retrospective clinic-
based study, 32–65% of patients with chronic and recurrent CGH perceived the impact of
their headache on function and relationships to be considerable or debilitating (37). The area
of function most affected in 87% of the patients was loss of productivity in paid work. The
considerable disability associated with CGH was also demonstrated at baseline by
participants of randomised controlled trials when measured using different patient-report
questionnaires(38-41).
This thesis characterises disability in migraine (Chapter Four), how it differs from non-
migraine headaches (Chapter Five), how it changes over time (Chapters Six) and its
measurement using patient-report outcomes (Chapter Seven). Collectively, the studies in
these chapters sought to broaden understanding of the burden of different headache types on
the individual level.
1.4. Clinical presentation and course of migraine and non-migraine headaches
Headache disorders that affect most individuals at least at one point of their lives (23) are
usually non-life threatening, mild or infrequent (42). In contrast, headaches that recur have
varied clinical presentations that may not be fully captured in the ICHD criteria (Table 1).
14
1.4.1. Clinical presentation of migraine and non-migraine headaches (TTH and
CGH)
1.4.1.1. Clinical presentation of migraine
Migraine presents as two main subtypes: migraine without aura and migraine with aura (8).
Both subtypes may occur a few episodes in a month (i.e., episodic migraine) or as many as 15
or more days in a month (i.e., chronic migraine) (8). Migraine with aura differs from
migraine without aura in that the headache in migraine with aura is preceded, accompanied
or, in rare cases, followed by transient neurologic symptoms. For both migraine subtypes, the
headache phases, and aura phase in the case of migraine with aura, are preceded by prodrome
(or premonitory) symptoms (8, 43). The prodrome symptoms may be general, such as
anorexia, neck pain or stiffness, or food cravings, or psychogenic, such as mood change,
fatigue, irritability, or neurogenic, such as difficulty concentrating, repetitive yawning (44-
47). Prodrome symptoms may also include those also associated with the headache phase
such as nausea, photophobia, or phonophobia (46). It is estimated that as much as 86.9% of
people with migraine experience these prodrome symptoms (45, 46). These symptoms may
again appear after the headache phase, as postdrome (or resolution) symptoms. Other typical
postdrome symptoms include weakness, lightheadedness and mild residual head discomfort
(43, 48). Postdrome symptoms appear to be as prevalent as prodrome symptoms, with as
much as 80% of people with migraine experiencing at least one postdrome symptom (46).
Further, nausea and/or vomiting during the headache phase and aggravation of the headache
by routine physical activity are considered the most characteristic symptoms of migraine
without aura, distinguishing it from other headache types (49, 50).
15
1.4.1.2. Clinical presentation of TTH
TTH may also occur a few episodes in a month (i.e., episodic TTH) or as many as 15 or more
days in a month (i.e., chronic TTH). (8). Of those features of TTH listed in Table 1, the
feature ‘not aggravating the headache by routine physical activity’ is considered its most
characteristic symptom, and that which most distinguishes it from migraine (49, 51, 52).
Unlike migraine, prodrome and postdrome symptoms are believed to be not typical of TTH
(53). The absence of prodrome and postdrome symptoms is consistent with the
characterization of TTH as a “featureless” headache (51). However, a clinical study reported
prodrome symptoms similar to those in migraine in as many as 87% of patients with episodic
TTH(44). In the same study, significantly fewer patients with TTH reported general
prodrome symptoms such as food craving, feeling cold, and diarrhoea than patients with
migraine. The similarity in prodrome symptoms between migraine and TTH led some authors
tohypothesise that these two headache types are not distinct entities and instead are the same
headache from the opposite severity spectrum (54, 55). This hypothesis is discussed later in
section 1.6.5. Still, similar features between migraine and TTH necessitate in-depth
characterisation of these headaches to arrive at a correct diagnosis and effective treatment.
Such characterisation is the focus of Chapter Five of this thesis.
Aside from TTH features listed in Table 1, another feature common to patients with TTH is
increased pericranial tissue tenderness that is present during the headache phase and even
between headache episodes (8). Among patients with TTH, increased tenderness [mean
tenderness score 25.6 (SD 5.8) out of 48] was demonstrated in cephalic and neck muscles and
the coronoid and mastoid processes (56). Pericranial tenderness is thought to increase with
16
headache frequency (57), although this was not replicated when data on headache frequency
were prospectively collected (56).
1.4.1.3. Clinical presentation of CGH
Whilst the scientific community is in general agreement as regards the clinical presentation of
migraine and TTH, the same cannot be said for CGH. Table 2 demonstrates this, with the
ICHD criteria differing from the CHISG criteria on clinical features that are considered
diagnostic for CGH (8, 13). Although the unilaterality of the headache that does not shift
sides is a confirmatory diagnostic criterion for CGH according to the CHISG criteria but not
for ICHD, this feature is recognised by ICHD as a typical presentation of CGH (8). Similarly,
ICHD recognises CGH as being typically reproduced by external pressure on the cervical
spine (8). Alternatively, pain radiating to the shoulder and arm, moderate, non-throbbing
pain, and history of neck trauma have also been suggested as being the most characteristic
associated symptoms of CGH (58).
It is therefore relevant to determine the extent to which patients demonstrate the above-
named features that are believed to be characteristic of migraine non-migraine headaches,
specifically TTH and CGH. Doing so would characterise these headaches better and possibly
clarify their distinction. With this in mind, we determined the extent to which study
populations in treatment efficacy trials demonstrated these characteristics, and other ICHD
criteria, in a systematic review presented in Chapter Two. To date, no study has investigated
how study populations are defined and therefore to whom evidence from the trials should
apply. Chapter Two fully explores this question.
17
1.4.2. Overlaps and variability in clinical presentation of migraine and non-
migraine headaches (TTH and CGH)
Despite the characteristic features of each headache type, migraine and common non-
migraine headaches, such as TTH and CGH, may have overlapping symptoms (14). For
example, characteristic features of migraine such as photophobia and aggravation of the
headache by physical activity are also present in 65% and 53%, respectively, in patients with
TTH (52). Other diagnostic criteria for migraine, namely headache episodes lasting 4 to72
hours, unilaterality, pulsating quality, and aggravation of headache by physical activity, were
also demonstrated by patients with TTH (33%, 11%, 23%, and 17%, respectively) (59).
Additionally, photophobia and phonophobia were also demonstrated in patients with TTH
(18% for both symptoms) (59) and CGH (19% and 28%, respectively) (60); and nausea and
vomiting were also present in CGH (up to 45.5% and 21.2%, respectively) (28). Conversely,
muscle tenderness, which is typically associated with TTH, was present to a notable degree in
patients with migraine (tenderness scores of 10–18 out of 24) (57). Headache provoked during
passive accessory intervertebral movement examination of the cervical spine, considered
diagnostic for CGH, was also present in 95% of patients with migraine and 100% of patients
with TTH (61). Moreover, all three headaches may present as unilateral headache that does
not shift sides (62). Despite the presence of features diagnostic for other headache types, it
must be noted that patients examined in the studies cited above still fulfilled the ICHD
diagnostic criteria for their respective headache types. Still, the overlapping symptoms may
make diagnosis challenging in some cases.
An individual with one headache type may also present with features characteristic of one or
more other headaches if these headaches coexist (63). It is estimated that 94% of individuals
18
with migraine have coexisting TTH (64). The coexistence between migraine and TTH has
been well recognised, that it has been included in the list of chronic overlapping pain
conditions by the National Institutes of Health and the United States of America Congress
(65). A population study, for example, demonstrated overlap of TTH with migraine without
aura in 83% of the sample and with migraine with aura in 75% of the sample (59). Similarly,
CGH has been shown to coexist with migraine and/or TTH in 1.8% of a population (31).
Aside from possible overlap in features between headache types, clinical presentation of
migraine, TTH and CGH may also be variable within the individual and between individuals
with the same headache type (49). Individuals with the same headache type may have
different clinical features considering the nature of the ICHD criteria where a combination of
features is used as basis for diagnosis. Therefore, not all diagnostic features are expected to
be present in individuals with a particular headache type. As well clinical presentations may
vary within the same individual and still fulfil the ICHD criteria for that particular headache
type. Of the three headache types, it is apparent from the classification rules in Table 1 that
clinical presentations that migraine has more variable symptoms than the non-migraine
headaches.
The apparent overlap of headache classifications and variability of headache features
provides another important reason to improve characterisation of migraine as distinct from
non-migraine headachessuch as TTH and CGH. Such characterisation of migraine was
explored in Chapters Five and Six.
19
1.4.3. Clinical course of migraine and non-migraine headaches
1.4.3.1. Clinical course of migraine
Aside from understanding the typical clinical features of migraine and non-migraine
headaches, understanding their clinical courses may also aid in characterising them better.
Evidence suggests that migraine does not progress. A 12-year retrospective study showed that
migraine episodes ceased in 29% of patients experiencing episodic migraine, and of those
who continued to experience migraine episodes 80% reported reduced frequency and. more
than 50% reported milder intensities, 1.6% developed chronic migraine (66). Similarly, a
prospective study showed that headache frequency decreased by more than 25% in almost
50% of patients whilst 16% reported an increase in headache frequency by more than 25%
(67).
1.4.3.2. Clinical course of TTH
Similar to migraine, evidence suggests that TTH generally does not progress (68). Population
studies showed that 45 to 48% remitted into less frequent or no headaches, 16 to 75% had an
unchanged frequency and 25 % progressed from episodic to chronic TTH (69, 70). Whilst
TTH does not seem to progress, TTH persists throughout young adulthood(71) or possibly
throughout life (72). Larger population studies are needed to know if TTH remits at some
point.
Whether migraine and TTH remit or progress is predicted by non-modifiable and modifiable
factors. For migraine, the most commonly cited factor in literature for progression of
20
migraine is high frequency, with headaches occurring 10–14 days per month having 20 times
the risk for progression compared to a frequency ≤ 4 days per month (73).Persistence of
chronic tension-type headache is associated with coexistence of other headaches (74),
medication overuse (74, 75), older age at baseline, duration longer than 6 years (75).
Other factors associated with progression of migraine or TTH to chronic daily headaches in
population studies are low level of education, arthritis, female, diabetes, previously married,
obese, and white people (76). Odds ratios for these factors for headache progression were
highest for low level of education [odds ratio (95% confidence interval) 3.35 (2.1 to 5.3)] and
lowest for white people [0.77 (0.6 to 1.0) for non-white people compared to white people]. Of
these factors, obesity was the most notable as it was also associated with five times higher
risk of developing new chronic daily headache, suggesting its importance as a potential target
of intervention to modify outcome in headaches (77). Conversely, remission after one year
from chronic to episodic headache was associated with higher education, diabetes, non-white
people, being married,and increasing age for females (78). Odds ratios for these factors for
remission was highest for higher education [odds ratio (95% confidence interval) 0.21 (0.1 to
0.5) for low education level] and lowest for increasing age for females [1.04 (1.01 to 1.06)].
It is difficult to explain how diabetes could be associated with remission. Nonetheless,
diabetes being a factor for both remission from and progression to chronic daily headache
suggests its potential as another target of intervention in headaches. For migraine, other factors
associated with remission are lower headache frequency [0.29 (0.11 to 0.75) for headaches
occurring 25–31 days per month compared to 15–19 headache days per month], absence of
allodynia [0.29 (0.11 to 0.75)] and non-use of preventive medications [0.41 (0.23 to 0.75) for
preventive medication use] (78).
21
1.4.3.3. Clinical course of CGH
In contrast to the studies done on clinical course of migraine and TTH, only one study to date
exclusively investigated the course of cervicogenic headache, observed in a cohort who had
whiplash injury. In this study by Drottning and colleagues (79), recovery from CGH was
shown to be slow, with 35% of patients still having CGH and further restrictions in cervical
range of motion six years after the whiplash injury. The authors hypothesised that it may take
as long as 10 years for the patients to be fully symptom-free. The trajectory of this slow
recovery showed a steep drop in the initial months followed by a slow decline, without
reaching full freedom from symptoms at six years. Results of this study suggest non-recovery
from CGH to be associated with younger age (mean age 44 years old versus 62 in those who
recovered from CGH); being female (82 % versus 71% in those who recovered). More
longitudinal studies with larger sample size of participants without associated whiplash injury
are needed to clarify the course of CGH. Given the trajectory of recovery shown in this study,
it would be interesting to validate the short-term course in individuals with CGH. In this
thesis, we investigated the six-month course of CGH and TTH compared with migraine in
Chapter Six.
Less is known too about short-term clinical course of migraine. One longitudinal
observational study has shown that clinical characteristics of migraine remain stable over 3
months, with a general trend toward improvement in disability (80). Additionally, improved
disability had a moderate positive association with headache frequency in 3 months. Further
evidence is required to build on these findings by identifying the short-term variations in
headaches. Thus Chapter Six of this thesis characterises how migraine changes over 6
months.
22
1.5. Cervical musculoskeletal impairments in migraine and non-migraine headaches
1.5.1. Rationale for considering cervical musculoskeletal impairments in
migraine and non-migraine headaches such as TTH and CGH
An understanding of impairments that are associated with particular headache types may help
further elucidate their pathophysiologic mechanisms. Among impairments that can be present
in both migraine and non-migraine headaches are those that affect the cervical
musculoskeletal system. This is due to the bidirectional relationship between nociceptive
input from the upper cervical spine and the brainstem, resulting from the convergence of
trigeminal and cervical afferents on to common neurons in the TCC. Cervical
musculoskeletal impairments may include neck pain and tenderness, deviations from normal
cervical articular movement and function and deviation from normal cervical muscle
structure and function.
The proposed role of cervical musculoskeletal impairments in TTH is illustrated by its former
descriptor ‘muscle contraction headache’. This term reflects the hypothesised origin of TTH
and the involvement of the muscles in the head and neck (8).Similarly, CGH is recognised as
a neck-related headache and its classification requires association of neck-related symptoms
and signs of impairments (8). Further studies characterising the nature of cervical
musculoskeletal impairments in migraine and non-migraine headaches are needed to
determine any similarity and difference between these headaches.
23
1.5.2. Neck pain
Understanding the nature of neck pain in headaches is particularly important because of the
widespread global prevalence of and disability due to neck pain itself (25).Neck pain has
been shown in population and clinical studies to be prevalent in individuals with migraine or
non-migraine headaches. Prevalence rates for coexisting neck pain with migraine ranged
from 16.7 % to as high as 72.6% (81-85).The association between migraine and chronic neck
pain ranged from odds ratio (95% confidence interval) 4.25 (3.84 to 4.70) (81) to 5.4 (5.2 to
5.6) (83). Whether neck pain is a comorbidity or is part of the migraine picture is still
contentious. One study supporting the notion that neck pain is part of the migraine episode
reported neck pain during the headache phase of the migraine in 69.4% of the patients (86).
Neck pain was also present among 36.1% of individuals with non-migraine headaches (82).
The frequent coexistence of neck pain in migraine and non-migraine headaches suggest the
relevance of specifying other impairments of the cervical spine that may be associated with
the headaches.
1.5.3. Cervical articular impairments
Cervical articular impairment, as used in this thesis, comprises restricted cervical range of
motion along the cardinal planes of movement and painful or restricted joint dysfunction
demonstrated during manual examination of the upper cervical spine or on rotation in flexion
at C1-C2 segment. There is strong evidence for the presence of cervical articular impairment
in headaches, especially for CGH. Their presence in CGH is expected and is among the
diagnostic criteria for CGH (8, 13). Cohort studies have demonstrated worse cervical articular
impairments in patients with pure CGH (87, 88) or CGH coexisting with one or more other
24
headaches (89) compared to individuals with migraine, TTH and controls. These impairments
included less cervical spine range of flexion (87), extension (87, 88) and rotation (88), and
pain on manual examination of the upper three cervical spine(87, 88). Individuals with CGH
also had significantly reduced range of motion at C1-C2 segment compared to individuals
with migraine and those with mixed headaches (90). These results from cohort studies were
consistent with a meta-analysis of studies, which further showed medium to large effect sizes
for differences in these impairments between individuals with CGH and controls (91).
Cervical rotation with cervical flexion showed the largest effect size [standardised mean
difference = 22.23 (95% confidence interval 22.73 to 21.73)] in favour of decreased range in
individuals with CGH compared to controls (91).
Evidence of cervical articular impairment is scant for TTH but suggests restrictions in
cervical range of motion in both episodic and chronic TTH. Specifically, restrictions in
cervical flexion, and right lateral flexion and rotation were demonstrated in episodic TTH
compared to controls (92) whilst restrictions in cervical rotation were demonstrated in
chronic TTH compared to episodic TTH and controls (93). In both studies, the groups which
demonstrated restrictions in cervical mobility also had reduced flexor head posture. This may
explain the difference in findings for episodic TTH and cervical mobility between the two
studies. One study also reported referred head pain on manual examination of the upper
cervical spine in 14 out of 14 participants with TTH (61). More studies are required to
validate these results.
Evidence of cervical articular impairment in migraine has been inconsistent. There is
evidence for restricted cervical rotation and upper cervical rotation in flexion in women with
episodic or chronic migraine compared to controls (94) and the presence of symptomatic
25
upper cervical joints in 80–100% of participants with migraine (61, 94). However, these
findings conflict with those indicating no cervical articular impairment in migraine compared
to controls (87, 88).
1.5.4. Cervical muscle impairments
Cervical muscle impairments in migraine and non-migraine headaches are also relevant to
characterise in relation to cervical articular impairment due to the role of the cervical
muscles, especially the deep muscles, in supporting the cervical joints. Cervical muscle
impairments may be deviations from normal physical structure, muscle behaviour
(comprising motor control aspects of contraction), and muscle function (including strength
and endurance).
1.5.4.1. Impairments in cervical muscle physical structure
Impairments in the structure of the cervical muscles have been observed in individuals with
TTH and CGH. In individuals with chronic TTH, atrophy of the rectus capitis posterior
muscleswas detected using magnetic resonance imaging(95). In individuals with CGH,
atrophy of the semispinalis capitis was also observed as reduced cross sectional area
measured using real-time ultrasound at C2 level on the symptomatic side in CGH(88). This
atrophy was not observed for other cervical extensors, namely,the longissimus capitisand
trapezius muscles of the cervical extensors, nor in migraine, TTH or controls. Muscle atrophy
in CGH was hypothesised to be associated with nerve supply coming from the dorsal rami of
the upper cervical nerves.
26
1.5.4.2. Impairments in cervical muscle behaviour
Impairments in muscle behaviour during contraction have strong evidence for CGH although
these have also been demonstrated in TTH and migraine. In CGH, large effect sizes
[standardised mean difference = -1.86 (95% confidence interval -2.74 to 0.99) were reported
for CGH compared to controls in terms of timing and activation of the deep cervical flexors
tested using the cranio-cervical flexion test (91). These findings were confirmed in more
recent studies that showed increased activity in the sternocleidomastoid in CGH, not
observed in migraine, TTH and controls (88). Similar impairments in muscle behaviour were
demonstrated in chronic TTH, where significantly lower pressure scores were achieved
during the cranio-cervical flexion test compared to controls (96).
Whilst cranio-cervical flexion test did not reveal impairments in muscles in migraine, one
impairment in muscle behaviour observed in episodic and chronic migraine was significantly
higher coactivation of cervical extensors during maximal cervical flexion compared to
controls(97, 98).Similarly, higher coactivation of antagonistic muscles was demonstrated in
chronic TTH during cervical flexion, and also during cervical extension (99).Whether or not
the increased muscle activity observed in these headache types is associated with any
comorbid cervical musculoskeletal disorder remains to be investigated.
1.5.4.3. Impairments in cervical muscle function
Impairments in cervical flexor function have been consistently demonstrated in CGH
compared to controls. These have been characterised as significantly worse than controls,
with large effect sizes indicating weaker cervical flexors [standardised mean difference =
27
-0.93 (95% confidence interval -1.33.to 0.54)] and lower cervical flexor endurance
[standardised mean difference = -1.56 (95% confidence interval -2.83 to 0.29)] in CGH (91).
These findings were confirmed in a more recent, larger cohort study (88).
One study (100) demonstrated similar findings for cervical extensors in CGH with large
effect sizes, indicating weaker cervical extensors [standardised mean difference = -1.01 (95%
confidence interval -1.59to -0.42)](91). Cervical extensor endurance in traumatic CGH was
also lower than controls (100). Aside from impaired strength and endurance, less extensibility
of the upper trapezius, scalenes and suboccipital extensors was also demonstrated in CGH,
not present in migraine with aura and controls (87).
Whilst some studies did not find impairments in cervical muscle function in TTH and
migraine compared to CGH, there is evidence for weakness of cervical extensors in TTH
compared to controls (101). Moreover, there is also evidence for weaker cervical
extensorsand of slower peak force generation for cervical flexion and left lateral flexion in
episodic migraine compared to controls (97).
Other cervical musculoskeletal impairments have been shown to be present in migraine, TTH
and/or CGH, including forward head posture (87, 93, 102), active trigger points (92, 93, 103),
and pressure pain threshold on sites relevant to cervical symptoms (87) but these are beyond
the scope of this thesis. Nevertheless, the cervical musculoskeletal impairments described
previously for migraine, CGH and TTH remain to be elucidated as to their role in headache
pathophysiology. Future studies may investigate whether these impairments are a prodrome,
comorbidity, cause, result, or feature of the headache phase. A step toward understanding the
nature of these impairments is exploring other cervical musculoskeletal impairments that may
28
be present in migraine and non-migraine headaches. This gap is particularly true for
migraine, where evidence of cervical musculoskeletal impairments is not as conclusive as for
TTH and CGH. The need to investigate cervical musculoskeletal impairments and their
assessment further is also suggested by an expert panel of physiotherapists which
nevertheless recommended a comprehensive examination of musculoskeletal impairments in
headaches (104). These findings point to the need for more evidence comparing cervical
musculoskeletal impairments in migraine and non-migraine headaches, especially for
impairment in cervical extensor function. Thus Chapters Five and Six describe cervical
musculoskeletal impairments in migraine and compare these with non-migraine headaches.
1.6. Overview of pathophysiology of migraine and non-migraine headaches
1.6.1. Common anatomy and physiology of headaches
Despite the different possible presentations and causes of headaches, it is believed that all
headaches involve the activation of the trigeminocervical complex (TCC) in the brainstem
(105, 106). Within the TCC, trigeminocervical neurons receive input from the periphery
through the trigeminal nerve, the upper three cervical nerves (Figure 1) and other cranial
nerves such as the facial, glossopharyngeal and vagus nerves (105, 106). The TCC makes
direct ascending connections with different areas in the brainstem, including the superior
salivatory nucleus and the ventrolateral periacqueductal grey (PAG), the rostral ventromedial
medulla (RVM), the nucleus cuneiformis, and with higher structures including several
hypothalamic and thalamic nuclei, which in turn make ascending connections with the cortex
(Figure 2). Thus activation of the second order neurons in the trigeminocervical neurons
29
results in transmission of nociceptive information to higher-order neurons in the thalamus.
This in turn, leads to activation of other higher-order pain centres in the cortex, such as the
frontal cortex, sensory cortex, insula, and cingulate cortex, resulting in headache (107).
Figure 1.The trigeminocervical nucleus, spanning the brainstem and spinal cord. It receives
afferents from the spinal tract of the trigeminal nerve and from the upper cervical
spinal nerves. It sends input to supraspinal centres through the trigeminothalamic
tract. Reprinted from The Lancet Neurology, Vol. 8, Bogduk N &Govind J,
Cervicogenic headache: an assessment of the evidence on clinical diagnosis,
invasive tests, and treatment, pp 959–968, 2009, with permission from Elsevier.
30
Figure 2. Overview of the peripheral and central nociceptive system involved in the
transmission and modulation of headache. Reprinted from Headache Currents, Vol.
2, Bartsch T, Goadsby PJ, Anatomy and physiology of pain referral patterns in
primary and cervicogenic headache disorders, pp 42–48, 2005, with permission
from SAGE Publications.
For chronic headaches, regardless of the headache type, there is also a common nociceptive
processing system that involves the peripheral and central nociceptive pathways. Peripheral
mechanisms involve the activation and sensitisation of peripheral nociceptors and Aδ and C
fibres (108, 109). The activation may be due to ischaemia, mechanical stimuli or chemical
mediators (110)whilst the peripheral sensitisation may be due to dysfunctional nociceptive
processing. The exact nature of the peripheral sensitisation remains unknown but may
involve increased nociceptive input from the periphery (for example the pericranial muscles,
as depicted in Figure 3), resulting in plastic changes in the trigeminal nucleus. As a
31
consequence, the normally inhibitory effect of low-threshold Aβ fibres on nociceptive
transmission in the spinal dorsal horn is altered to a pain stimulatory effect, and the response
to nociceptive Aδ and C fibres is potentiated. The amplified nociceptive stimulation of
supraspinal structures, such as the TCC and in the thalamus, results in central sensitisation
(111). It appears that this central sensitisation also involves the activation of descending
modulating pathways in the RVM and in the PAG such that nociceptive input is amplified
and the anti-nociceptive input that would normally inhibit pain in a healthy nociceptive
system is inhibited. Together, these mechanisms may induce and maintain the chronic
headache. Central sensitisation due to amplified nociceptive input and disinhibition from the
descending modulating systems may result in clinical features such as hyperalgesia, increased
sensitivity to typically noxious stimuli. Additionally, when the TCC is sensitised, stimulus
that are normally noxious such as movement or touch may trigger a headache. This increased
sensitivity to typically non-noxious stimuli, allodynia, is manifested, for example, as
hypersensitivity during shaving or when wearing glasses (110, 112).
32
Figure 3.Dysfunctional nociceptive processing in chronic headaches. Important alterations
from the normal nociceptive state are presented in bold. V, Trigeminal nerve; C2
and C3, second and third cervical segment of the spinal cord; PAG, periaqueductal
grey; RVM, rostral ventromedial medulla. Reprinted from Cephalalgia, Vol. 20,
Bendtsen L, Central sensitization in tension-type headache — Possible
pathophysiological mechanisms, pp 486–508, 2000, with permission from SAGE
Publications.
Beyond the TCC, there are other anatomic structures and functional interactions involved in
the pathophysiology of the different headache types. Mechanisms that are specific for each
headache type are believed to be manifested as differences in clinical features. Different
theories have been proposed for the pathophysiology of specific headache types but so far
these are still inadequate in clarifying the entire range of possible features of a headache
within and between individuals or the definite mechanisms that initiate, propagate and
terminate the headache. Until these features and mechanisms are conclusively elucidated,
33
headache assessment, diagnosis and treatment may remain nonspecific and inadequate. Thus
pathophysiology of headaches remains a dynamic research area. The current widely known
pathophysiologic theories for migraine, TTH and CGH are briefly discussed in sections
1.6.2–1.6.4 below.
1.6.2. Overview of pathophysiology of migraine
1.6.2.1. Role of the trigeminovascular system
The currently accepted theory on the pathophysiology of migraine implicates the activation
and sensitisation of the trigeminovascular system. (TGVS) (Figure 4) (111, 113). The TGVS
consists of the trigeminal ganglion (TG) projecting peripherally to cerebral blood vessels and
dura mater innervated by the trigeminal nerve and centrally to the TCC in the brainstem and
spinal cord. Peripheral nociceptive input in migraine comes from nociceptors and nociceptive
A-δ and C fibres innervating the intracerebral blood vessels and dura mater (113).
Nociceptive input is then transmitted to the trigeminal nerve, the trigeminal ganglion, and
synapses on second-order neurons in the TCC (53).
34
Figure 4.Pathophysiology of migraine.The key pathways for the pain are the
trigeminovascular input from the meningeal vessels, which passes through the
trigeminal ganglion and synapses on second-order neurons in the trigeminocervical
complex in the brainstem. These neurons, in turn, decussates in the brainstem and
form synapses with neurons in the thalamus. Reproduced with permission from
Goadsby PJ, Lipton RB, Ferrari MD. Migraine — Current understanding and
treatment.N Engl J Med. 2002;346:257–270. Copyright Massachusetts Medical
Society.
35
1.6.2.2. Mechanisms responsible for headaches phases
The exact mechanisms responsible for the premonitory, aura, headache, and postdrome
phases of headaches, and transitioning between these phases, remain unclear. Current
evidence suggests that mechanisms for these phases overlap (43). During the premonitory
phase, it is generally believed that the central nervous system mediates the release of
dopamine and activity of and therefore blood flow in the hypothalamus increase (114). This
increased activity in the hypothalamus is part of a bigger picture of brain excitability before
the headache phase. Just before or during the aura phase, regional cortical cerebral blood flow
decreases, usually starting posteriorly and progressing anteriorly (8). This decrease in blood
flow is above the threshold for ischaemic injury. The decrease in blood flow gradually
progresses into increased blood flow over a period of hours. This change in regional cortical
cerebral blood flow is believed to be due to cortical spreading depression (CSD). In CSD, a
slow short-lasting depolarization wave propagates across the cortex that is followed by a
period of inactivity. In migraine forms that do not have auras, a similar mechanism is
postulated to be present but inactive. Animal studies suggest that CSD could be the
mechanism activating the TGVS. This probable link provides an explanation for the headache
that follows aura in migraine. As previously described, the headache phase of migraine
involves activation and sensitisation of meningeal nociceptors and afferents say by
mechanical stimuli. The sensitisation of meningeal afferents provides a mechanism that may
explain the throbbing nature of the migraine headache as well as the exacerbation of the
headache during events (e.g., coughing or sudden head movements) that increase intracranial
pressure (111). Experiments showed that activation of the meningeal nociceptors may initiate
a cascade of events leading to the release of inflammatory mediators. This neurogenic
inflammation then results in the sustained activation and sensitisation of the meningeal
36
afferents, which then activates and sensitises second-order and third-order trigeminocervical
neurons. Activation of the trigeminocervical neurons then activates different areas of the
brain, resulting in headache. After the headache phase, symptoms occur comprising the
postdrome phase. The few studies about postdrome phase suggest that this phase is linked
with persistent changes in brain activity past the headache phase (115). These changes
include bilateral posterior cortical hypoperfusion, midbrain and hypothalamic activation, and
increased blood flow in the visual cortex. The overlap of postdromal symptoms with
premonitory symptoms sets the scene for further investigation of the nature of postdromal
symptoms.Therefore it is thought that migraine is fundamentally due to an abnormality in
central processing of not necessarily abnormal input. Yet in some cases, as described earlier,
meningeal nociceptors may also be involved (Figure 2). The exact mechanisms of
sensitisation in migraine remain unknown.
1.6.2.3. Role of neurochemicals in migraine pathophysiology
Another area in migraine pathophysiology that remains inadequately understood is the
relationship between migraine and alterations in neurochemicals in the central nervous
system, particularly the possible imbalance between excitatory and inhibitory
neurotransmission (116, 117). The activation of the TGVS is thought to release calcitonin
gene-related peptide (CGRP) and substance P which, in turn, cause further vasodilation and
neurogenic inflammation through the secretion of inflammatory mediators such as serotonin,
adenosine diphosphate, platelet-activating factor, nitric oxide, and interleukins. The
vasodilation and neurogenic inflammation further sensitise the neurons in the TG, followed
by the neurons in the TNC in the brainstem (116). It is through this mechanism that CGRP, in
particular, is postulated to transmit nociceptive information.
37
As regards excitatory-inhibitory neurotransmitter imbalance, there is evidence of a number of
anomalies in metabolism of excitatory neurotransmitters in migraine compared with controls.
These include higher glutamate-to-glutamine ratios in the occipital cortex (118) and altered
levels of N-acetyl-aspartylglutamate in the anterior cingulate cortex as well as the insula
(119). In contrast to evidence for excitatory neurotransmitters in migraine, the role of the
principal inhibitory neurotransmitter gamma aminobutyric acid (GABA) has only been
indirectly demonstrated, at best. For example, increased salivary GABA levels have been
reported in people with migraine without aura during attacks, compared to interictal periods
and to people with non-migraine headaches (120). These results suggested that increased
GABA metabolism may somehow be a protective mechanism to limit symptomatic episodes.
Increased levels of GABA in the cerebrospinal fluid (CSF) have also been demonstrated in
people with migraine compared to controls (121). The increased CSF GABA was purported
to be indicative of increased GABA concentration in the brain due to ischemia.
Despite these findings, the role of GABA in migraine has not yet been fully established
because of the lack of studies directly measuring GABA levels in the brain (122). Thus the
possible role of GABA in pathophysiology was investigated in a study presented in Chapter
Three in this thesis, where GABA levels in the brain were compared between migraine and
controls.
1.6.3. Overview of pathophysiology of a non-migraine headache: TTH
Details of mechanisms of TTH, especially of its initiation, are still under debate. The
prevailing theory is that both peripheral and central nociceptive mechanisms contribute to
38
TTH, with peripheral nociceptive mechanisms being most likely responsible for episodic
TTH whereas central nociceptive mechanisms being most likely responsible for chronic TTH
(8, 93). An example of activation of the peripheral system in TTH is a slightly increased
muscle activity, which may result in microtrauma of muscle fibres and tendon, causing
accumulation of chemical mediators. Such events may then activate and sensitise the Aδ and
C fibres (123) and eventually cause increased myofascial tenderness, a feature of a specific
subtype of TTH (8). Prolonged nociceptive impulses from the myofascial tissues result in
summation of such impulses leads to sensitisation of the second-order neurons of the
trigeminal nerve and second and third cervical segment of the spinal cord. This, in turn,
results in increase nociceptive transmission to the supraspinal structures such as the thalamus
and sensory cortex, and decreased supraspinal nociceptive modulation (108) resulting in
headache.
The role of central sensitisation in TTH is only recently recognised. As such, central
sensitisation represents additional shared anatomic and physiologic substrates between TTH
and migraine and fuels the debate on whether migraine and TTH are distinct headache types
or belong to the same headache type with opposing severities. The arguments for and against
this view of migraine and TTH being indistinct headache types are presented later in section
1.6.5.
1.6.4. Overview of pathophysiology of a non-migraine headache: CGH
Compared to migraine and TTH, pathophysiologic mechanisms for CGH are better
understood. The most important differentiator of CGH from migraine and TTH is the
perception of pain in the head referred from a disorder in the cervical spine (34). The
39
mechanism for referral of pain from the cervical spine to the head involves the convergence
between afferents from the upper cervical nerve roots and trigeminal afferents on common
neurons in the TCCin the brain stem (Figure 1) (58, 106). Information received in the TCC
from the upper cervical spine may relate to changes in muscle (spasm or tension), head and
neck posture, neck strain, or nerve irritation. Such information on dysfunction in the upper
cervical spine can cause sensitisation of the TCC.
However, the role of the cervical spine as a generator of the headache in CGH and its
diagnosis still lacks consensus (124, 125). One argument against the cervical spine as a
headache generator is the shared cervical musculoskeletal impairments between CGH and
other headache types(29, 88, 126), as described earlier in section 1.5. Another argument is
that not all patients with upper cervical spine impairments complain of headache (125). For
these reasons, it is possible that the cervical spine and a central mechanism are required to
produce CGH (125, 127). Correspondingly, central sensitisation has been demonstrated in
chronic forms of CGH, as previously described. Central sensitisation was evidenced by
bilateral and generalised hyposensitivity, manifested as higher thermal detection thresholds
(128). These results need to be validated in larger studies to hopefully clarify the exact
mechanisms of central sensitisation in CGH.
1.6.5. Alternative hypothesis on shared pathophysiology of migraine and TTH:
Continuum theory
Migraine and TTH are classified as two distinct headache types in the ICHD. However, many
have challenged this notion that migraine and TTH are two distinct entities and instead have
proposed that they are the same disorder in opposite ends of the severity spectrum, with
40
migraine in the more severe end of the spectrum, and TTH in the less severe end (55). This
alternative view has been referred to as the convergence hypothesis(54) or continuum severity
model (129).
1.6.5.1. Arguments for the continuum severity model
A review of the diagnostic features of migraine and TTH (Table 1) may be interpreted by
proponents of the convergence hypothesis as supporting their position. The diagnostic
features of TTH are mostly absence or milder expressions of the diagnostic features of
migraine (8, 51). Other overlaps between migraine and TTH have been noted, which to some,
provide evidence for the convergence hypothesis. These overlaps include similarities in
clinical features where features considered diagnostic for migraine are present in TTH and
features typically associated with TTH are present in migraine [e.g. (63)]. One study revealed
that the convergence hypothesis is demonstrated more in young adults with chronic
headaches (129). Some prodrome symptoms are also similar between migraine and TTH (44).
Having similar clinical features also challenge the notion of distinct pathophysiologic
mechanisms for these two headache types, and therefore their being distinct headache types.
Cady and colleagues propose that episodic TTH may evolve to migraine with increasing
severity and central sensitisation(54). Response to treatment has also been cited as a
similarity between the two with both being responsive to sumatriptan especially for migraine
with neck pain (130). Another argument for the convergence hypothesis is the coexistence of
migraine and TTH (e.g. 94% of individuals in a population study (64).
41
1.6.5.2. Arguments against the continuum theory
Despite these similarities between migraine and TTH supporting the convergence hypothesis,
there is evidence that migraine and TTH differ in their epidemiologic profile, specifically in
terms of age and sex distribution. Notwithstanding the difference in epidemiologic profile,
the strongest evidence for migraine and TTH being distinct lies on their genetic heritability.
Migraine has been shown to have as high as 50% heritability, with identified genetic markers
for familial hemiplegic migraine (117). Similarly, a genetic population study showed
concordance for ETTH and having no TTH among monozygotic twins (131).
1.6.6. Gaps in evidence on pathophysiology addressed in this thesis
The debate on whether migraine and TTH are distinct entities or not is still ongoing. Further
genetic profiling of these two headache types is critical in resolving the question on their
being distinct. Until genetic biomarkers are fully elucidated, an enhanced clinical
characterisation of the migraine and TTH may help in understanding how similar or distinct
they are. Moreover, characterisation of the natural course of these two headaches, especially
in cases which have coexisting diagnostic features for both, would help identify their
distinction. To contribute to this debate, this thesis presents a characterisation of cervical
musculoskeletal impairments and pain and disability in migraine versus non-migraine
headaches (including TTH) in Chapter Five and a comparison of their clinical course over 6
months in Chapter Six.
Further evidence on the pathophysiology of migraine, TTH and CGH is required toward a
full understanding of the exact mechanisms causing the headache. For migraine, the
42
propagation and termination of each attack also remains to be fully elucidated. The need to
fully understand the pathophysiology of headaches also highlights the need to identify
biomarkers for these headaches(111). Therefore the potential of one neurochemical, GABA,
as a biomarker is explored in Chapters Three and Four. Further, hypotheses regarding
pathophysiologic mechanisms might be generated by comparing clinical characteristics in
these headaches. Thus the clinical characteristics of migraine are compared with non-
migraine headaches in Chapters Five and Six.Among the characteristics examined to better
understand pathophysiology was the extent of central sensitisation symptoms measured using
patient-report outcomes.
1.7. Assessment to characterise migraine and non-migraine headaches
1.7.1. Interview
Because diagnosis using the ICHD involves differentiating one headache type from others
primarily based on headache features, the most essential element of assessment is therefore
patient history, through interview (132). For example, the clinician asks about headache
frequency, location, quality and accompanying symptoms. The clinician then integrates and
evaluates information from patient history to determine whether the headache is most likely
primary or secondary. History is particularly critical for primary headaches like migraine and
TTH which are not associated with objective clinical features that would allow objective
basis for diagnosis. Based on patient history, the clinician determines if the headache is
primary or secondary. This step in the diagnosis may require physical and neurological
examination (133). Once the clinician has determined whether the patient has primary or
43
secondary headache, the clinician then determines the most likely headache diagnosis. The
ICHD lists “Not better accounted for by another ICHD-3 diagnosis” as the final criterion for
all headache types to remind clinicians to always consider other possible diagnoses (8).
1.7.2. Headache diary
Information on headache features from an interview may be supplemented through headache
diaries (17). The advantage of the headache diary is that it prospectively collects headache
symptoms and responses to the headache. The prospective collection of information reduces
the recall bias which may be present during interview. The headache diary is also useful in
closely following the behaviour of symptoms over time. (133). Doing so may help
scrutinisevariability in patient symptoms.
1.7.3. Physical examination tests for cervical musculoskeletal impairments
An international panel of clinical and research physiotherapy experts has recommended a
number of physical examination tests that may be useful in assessing patients with headaches,
regardless of headache type (104). This recommendation is presumably related to evidence of
the prevalence of cervical musculoskeletal impairments in headaches, as discussed earlier in
section 1.5. The physical examination tests deemed useful or extremely useful by the expert
panelwere manual joint palpation, cervical flexion-rotation test,active range of cervical
movement,passive physiological intervertebral movements, reproduction and resolution of
headache symptoms, cranio-cervical flexion test,combined movement tests, head forward
position, trigger point palpation, muscles tests of the shoulder girdle, and screening of the
44
thoracic spine. It was not specified whether these tests are useful for diagnosis or for
assessing treatment outcomes.
Of these tests, manual examination at C1/C2 segment of cervical spine and measurement of
muscle length of the pectoralis minor muscle demonstrated discriminative ability for CGH
versus migraine with aura and controls with a sensitivity of 80% (87). This finding was
corroborated by another cohort study showing discriminative ability of a combination of
manual examination of C0/C1 to C3/C4 segments, cranio-cervical flexion test and cervical
extension range of motion measurement for CGH compared to migraine, TTH and controls
with a sensitivity of 100% and specificity of 94% (88). In addition, flexion rotation test was
also found to have good diagnostic accuracy for CGH versus migraine and mixed headache
forms when used by an experienced examiner (area under the curve = 0.85 (95%
confidence interval 0.75 to 0.95); p< 0.001). (90). Aside from tests found discriminatory for
cervicogenic headache, tests for cervical muscle behaviour and function, especially of the
cervical extensors, require further investigation.
1.7.4. Self-report questionnaires
Self-report questionnaires may be used to elicit information directly from the patient about
the nature of his or her headache experience. The outcomes that can be assessed in headaches
using self-report questionnaires may include quality of life, satisfaction about the treatment,
pain beliefs, to name a few (133). The use of self-report questionnaires is consistent with
recognising that headache is a subjective experience.
45
1.7.5. Assessment of migraine and non-migraine headaches used in this thesis
Participants of studies presented in Chapters Six and Seven of this thesis completed a
headache diary to provide information about their headache symptoms and disability of
participants over 6 months. Information from the diary supplemented information obtained
from the participants during the interview and using a self-report questionnaire. Self-report
questionnaires were used in this thesis to assess personal factors that possibly influence the
patient experience. These self-report questionnaires are presented in Appendices 4 and 5. The
outcomes collected from the self-report questionnaires are presented in Chapters Four
through Seven of this thesis. Of the tests found discriminatory for CGH and recommended by
the expert panel for headaches, we employed manual joint palpation, the cranio-cervical
flexion test, the cervical flexion-rotation test and active range of cervical movement to
characterise migraine and their distinction from non-migraine headaches. These tests are
briefly described in Appendix 5. Findings from these assessments of cervical musculoskeletal
impairments in migraine and non-migraine headaches are reported in Chapters Five and Six.
In an attempt to fill the gap in evidence about cervical muscle behaviour and function,
especially of the extensors, we also included such tests in the physical examination of
participants in the studies presented in Chapters Five and Six.
46
1.8. Recognising factors that influence the patient experience in headaches
1.8.1. The importance of assessing more than the diagnostic criteria
Existing headache classification systems were designed to focus on describing headache
features and associated symptoms of each headache episode. Whilst such information is
generally considered adequate for diagnosis, it is arguably inadequate for understanding the
impact of the symptoms on the person (133). In headaches that persist and recur like
migraine, TTH and CGH, the impact of the headache may extend to all domains of life and
factors other than the headache symptoms may influence the patient experience of the pain
(133). Therefore other factors influencing the headache experience and the response to the
headache must be assessed to enhance the understanding of the patient experience.
1.8.2. Factors influencing the patient experience
1.8.2.1. Disability
Disability pertains to how a health condition affects the person on the ability to function at
home, at work or socially and how the person responds to the condition (133). The World
Health Organisation defines disability in the International Classification of Functioning,
Disability and Health (ICF) as an umbrella term for a person’s functioning in society that
encompasses impairments, activity limitation and participation restriction (134). Impairments
are deviations from typical body structure or function, activity limitations are restrictions in
the ability to perform daily activities in a manner that is considered efficient and competent,
and participation restriction is the inability to perform roles expected by society according to
47
a person’s context (134). Defining disability in this manner recognises that a health condition
affects a person according to biomedical factors that are present and personal and
environmental factors that may influence the person’s response to these biomedical
factors(133). Disability must therefore be assessed because it cannot be fully explained by
headache frequency, intensity and symptoms (135). The headache research community seems to
agree with the recommendation of measuring disability and functioning as a secondary outcome
measure in headache trials (20, 21). Some even argue that disability is the most important
indicator of severity of the disorder (136) as disability may differ even among individuals with
the same type and severity of headache.
1.8.2.2. Pain
When assessing pain in patients with headaches, we recognise that the person is living
through an unpleasant and complex experience (137). The complexity of the pain experience
rests on its subjective nature and the involvement of different dimensions contributing to the
pain experience. The sensory-discriminative dimension contributes the sensation of the
nociception. This in, turn, is modified by the cognitive-evaluative dimension contributes the
meanings attached to the pain from past experiences or knowledge, and the motivation-
affective dimension contributes to emotions associated with the pain which relates with the
escape or attack response to the pain.
48
1.8.2.3. Central sensitisation symptoms
A construct related to pain is central sensitisation. The occurrence of central sensitisation was
presented in an earlier section. Briefly, central sensitisation involves the hypersensitivity of
the central nervous system to stimuli which may or may not be known to cause pain (138).
Examples of manifestations of central sensitisation in patients with headaches are
hyperalgesia (139) such as headaches associated with increased tenderness to palpation, and
cutaneous allodynia (112) such as experiencing pain or any unpleasant sensation on the skin
during a headache episode attack when tying the hair in a ponytail or being exposed to heat in
the kitchen.
1.8.2.4. Personal factors contributing to the headache experience
The broad view of disability, as defined above, has implications on assessing a diverse range
of information from patients with headaches. A comprehensive assessment may take into
account factors including biomedical factors such as head pain characteristics and associated
symptoms, and personal and environmental factors including but not limited to the extent of
comorbidities, sleep quality, level of physical activity, and emotional state and response to
pain such as depression, anxiety and stress, Such comprehensive assessment would allow
better understanding of the patient’s experience of the headache and therefore contribute to
managing that experience. In keeping with a patient-focused management approach, the
assessment of these factors should also include information that are coming directly from the
patient and that are meaningful to the patient.
49
1.8.3. Biomedical and personal factors assessed in this thesis
A comprehensive assessment of the patient experience, incorporating biomedical and
personal factors, was done in this thesis. For cross-sectional and cohort studies presented in
this thesis (Chapters Four through Seven), headache characteristics were assessed through an
interview and through a self-report questionnaire. Additional biomedical factors assessed
using self-report questionnaires were pain and central sensitisation. Other biomedical factors
assessed in studies presented in Chapters Five andSix were cervical musculoskeletal
impairments using physical examination tests. These tests were previously shown to be
discriminatory for CGH (87, 88, 90) and recommended by an international panel of experts as
appropriate for people with headaches (104). Personal factors were assessed using self-report
questionnaires in studies presented in Chapters Four, Five and Six. These personal factors
were comorbidities, sleep quality, level of physical activity, and emotional state. Lastly,
disability was assessed using headache-specific and generic questionnaires in studies
presented in Chapters Four through Six. The meaningfulness of assessing disability was
further investigated in Chapter Seven by looking at how disability changes over six months
and the ability of the questionnaire to detect clinically relevant change. Such
multidimensional assessment may improve characterisation of each headache type,
particularly if there are notable differences between headaches types. Whether such
differences exist between migraine and non-migraine headaches, namely TTH and CGH, was
explored in this thesis.
50
1.9. Summary
In summary, migraine and non-migraine headaches,specifically TTH and CGH, are the most
prevalent headaches which have in common some pathophysiologic mechanisms and clinical
features related to cervical musculoskeletal impairments. Migraine, TTH and CGH cause
significant disability partly due to a lack of full understanding of their pathophysiological
mechanisms, their clinical characteristics that may help distinguish them, and other factors
that may influence the impact of the headache. As such, headache classification and diagnosis
of these headaches may be difficult for some cases. A comprehensive snapshot of the state of
the art in the application of the headache classification system in defining migraine, TTH and
CGH populations in headache trials is reviewed in Chapter Two. Results of this review
guided the definition of our study populations in studies presented in this thesis. A candidate
biomarker for migraine was investigated in Chapter Three. The good diagnostic accuracy of
the candidate biomarker for migraine stimulated the continuation of its validation as a
biomarker in Chapter Four by determining its association with clinical characteristics of
migraine. The clinical characteristics that correlated with the candidate biomarker in Chapter
Four were included as outcome measures in the cohort study characterising migraine and
non-migraine headaches in Chapter Five. The findings in Chapter Five that disability differed
between migraine and non-migraine headaches and changed over 6 months in Chapter Six led
to investigating the meaningfulness of measuring disability over time in migraine and non-
migraine headaches in Chapter Seven. Therefore this thesis substantiates the current standard
in classifying headaches, adds new evidence on the pathophysiologic mechanisms of
migraine and the clinical course of migraine and non-migraine headaches, and confirms and
augments what is known about the extent of cervical musculoskeletal impairments and
disability in migraine and non-migraine headaches.
51
1.10. Aims of the thesis
The broad aim of this thesis was to characterise migraine on the basis of its neurochemical
profile, cervical musculoskeletal impairments and patient experience as distinguished from
non-migraine headaches.
The objectives were to:
1. Describe how headaches are defined in clinical trials (Chapter Two)
2. Compare levels of brain neurochemicals in migraine to controls (Chapter Three)
3. Explore the relationship between brain neurochemicals and relevant disease
characteristics of migraine (Chapter Four)
4. Characterise cervical neck impairments and patient experience in migraine compared to
non-migraine headaches and controls (Chapter Five)
5. Characterise the six-month clinical course of migraine and non-migraine headaches and
the factors associated with the clinical course (Chapter Six)
6. Examine changes in disability over six months in migraine and non-migraine headaches
(Chapter Seven)
52
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66
CHAPTER TWO
Definitions and Participant Characteristics of Frequent
Recurrent Headache Types in Clinical Trials:
A Systematic Review
Chapter Two is the peer reviewed version of the following article: Aguila ME, Rebbeck T,
Mendoza KG, De La Peña MG, Leaver AM. Definitions and participant characteristics of
frequent recurrent headache types in clinical trials: A systematic review.
Cephalalgia.Epub2017 Apr 25. doi: 10.1177/0333102417706974, which has been published
in online form ahead of print at
http://journals.sagepub.com/doi/pdf/10.1177/0333102417706974
67
Authorship Statement
As co-authors ofthe paper “Definitions and participant characteristics of frequent recurrent
headache types in clinical trials: A systematic review”, we confirm that Maria Eliza Ruiz
Aguila has madethe following contributions:
• Conception and design of the research
• Acquisition of data
• Analysis and interpretation of data
• Drafting and revising of the manuscript and critical appraisal of its content
Signed: Trudy Rebbeck Date: 31 March 2017
Signed: Kristofferson G Mendoza Date: 31 March 2017
Signed: Mary-Grace L De La Peña Date: 31 March 2017
Signed: Andrew M Leaver Date: 31 March 2017
68
Manuscript Title: Definitions and participant characteristics of frequent recurrent headache
types in clinical trials: A systematic review
Authors: Maria-Eliza R Aguila1,2, Trudy Rebbeck1,3, Kristofferson G Mendoza2, Mary-Grace
L De La Peña2, Andrew M Leaver1
Authors Institutional Information:

1
University of Sydney Faculty of Health Sciences
75 East Street, Lidcombe, New South Wales 2141 AUSTRALIA
2
University of the Philippines College of Allied Medical Professions
Pedro Gil Street, Manila 1004 PHILIPPINES
3
John Walsh Centre of Rehabilitation Research, Kolling Institute of Medical Research
Royal North Shore Hospital, University of Sydney
Corner Reserve Road and First Avenue, St. Leonards, New South Wales 2065 AUSTRALIA
Corresponding Author:
Maria-Eliza R Aguila
[email protected]
Telephone number: (+612) 9351 9010
Fax number: (+612) 9351 9601
69
Abstract
Background: Clear definitions of study populations in clinical trials may facilitate application
of evidence to clinical populations. This review aimed to explore definitions of study
populations in clinical trials on migraine, tension-type headache, cluster headache, and
cervicogenic headache.
Methods: We performed a systematic review of clinical trials investigating treatment efficacy
for migraine, tension-type headache, cluster headache, and cervicogenic headache. We
extracted data on diagnosis, inclusion criteria and baseline headache characteristics.
Results: Of the 229 studies reviewed, 205 studies (89.5%) defined their populations in
adherence to the International Classification of Headache Disorders (ICHD) criteria. Some
studies (n = 127, 55.5%) specified diagnosing through interview, clinical examination and
diary entry. The most commonly reported inclusion criteria were pain intensity for migraine
and tension-type headache studies (n = 123, 66.1% and n = 21, 67.7%, respectively), episode
frequency for cluster headache studies (n = 5, 71.4%), and neck-related pain for cervicogenic
headache studies (n = 3, 60%). Few studies reported details on the extent to which diagnostic
criteria were present at baseline.
Conclusions: ICHD is routinely used in defining populations in headache studies. Details of
baseline headache characteristics were not as consistently reported.
Key words: Patient selection, International Classification of Headache Disorders, migraine,
tension-type headache, cluster headache, cervicogenic headache
70
Introduction
Migraine, tension-type headache, cluster headache (1) and cervicogenic headache (2) are
among the most commonly seen headaches in primary care and specialist clinics. Effective
treatment of these headaches relies on correct diagnostic classification. Increased headache
research over the past two decades (3) has contributed to improving the classification system
for headaches such as the International Classification of Headache Disorders (ICHD). The
ICHD, now on its third edition (beta version), provides a framework to standardize headache
classification (4,5) and addresses the challenge of distinguishing headache types. A
classification framework such as ICHD is important to ensure homogeneity of participants in
clinical studies investigating treatment efficacy.
Despite this improvement, classification of headaches using ICHD may be
challenging for certain cases given that the classification system is based on clinical features
(6). For one, a headache type may coexist with one or more other headache types (7). Further,
symptoms vary within and between individuals with the same headache type (8).
Additionally, some headache features may overlap, especially for frequent recurrent and
disabling headaches such as migraine, tension-type headache, cluster headache and
cervicogenic headache (6,9). It is therefore important to examine how study populations are
defined in clinical trials. Details on definitions of study populations may confer better
understanding of current criteria used to classify headaches. This understanding, in turn,
would potentially increase awareness on the nature of headaches between study populations
and guide to whom the inferences from the trials could be applied.
The primary objective of this systematic review, therefore, was to explore and
describe the definitions of study populations in clinical trials. In particular, this review aimed
to explore the eligibility criteria for study populations of frequent recurrent headaches,
namely migraine, tension-type headache, cluster headache, and cervicogenic headache. The
71
secondary objective of this review was to describe baseline characteristics of participants
enrolled in clinical trials in terms of headache features listed as ICHD diagnostic criteria.
72
Methods
Protocol registration
The protocol for this systematic review was registered with PROSPERO (registration number
CRD42014009167).
Eligibility criteria
We included research articles that were intervention studies (controlled studies or prospective
cohort studies) that described participants as having ‘primary headache’, ‘migraine’, ‘tension-
type headache’, ‘cluster headache’ or ‘cervicogenic headache’. Inclusion was limited to
studies published in English in peer-reviewed journals from the time of introduction of
ICHD-II in 2004. When this second edition of classification was released, it was
recommended for use as standard definitions of headaches for clinics and research (4).
We excluded articles that had cohorts other than the diagnoses of interest for this
review and articles that presented data for the same cohort as an earlier publication already
included in the review.
Information sources
Relevant articles were identified by searching the following electronic databases from 2005
to April 2015: Cochrane Library, Medical Literature Analysis and Retrieval System Online
(MEDLINE), Cumulative Index to Nursing and Allied Health Literature (CINAHL). The
Allied and Complementary Medicine Database (AMED), Embase, Physiotherapy Evidence
Database (PEDro), and Web of Science. In addition, researchers scanned the “related
articles” link of databases and SCOPUS to identify reports citing the included studies.
Search strategy
73
We used a sensitive search strategy using a combination of Medical Subject Headings
(MeSH) and words “primary headache” OR “migraine” OR “tension-type headache” OR
“cluster headache” OR “cervicogenic headache” and related terms. The search was limited to
‘peer-reviewed publication, 2005 to 2015’ and ‘humans’ (Appendix A) and conducted by a
single investigator (MA).
Study selection
Two reviewers (MA and GD) removed duplicate citations and independently determined
eligibility of retrieved articles by applying the inclusion criteria through title and abstract
screening in EndNote™ X7.3 (Thomson Reuters. Endnote. New York: Thomson Reuters;
2015). Two other reviewers (TR and AL) were consulted for articles that did not clearly meet
the inclusion criteria. The full text of the remaining citations was retrieved and independently
assessed by two reviewers (MA and AL or TR or KM or MD). Disagreement between the
reviewers on study selection was resolved by a third researcher (TR or AL).
Data extraction
A data extraction spreadsheet was designed and pilot tested by all reviewers. Data were
extracted independently by two reviewers (MA and AL or TR or KM or MD). Disagreement
between the reviewers on extracted data was resolved by a third researcher (TR or AL).
Data extracted included study and participant characteristics (Appendix B). Study
characteristics included research design, sample size, intervention and control, method of
headache diagnosis, and inclusion and exclusion criteria for the study. Participant
characteristics comprised demographic information and headache features of the participants
at baseline. Headache features included the diagnostic criteria for the each headache type
according to ICHD-II (4). Studies were grouped by diagnosis for descriptive analysis. Data
74
on the process of diagnosis and inclusion criteria used in the clinical studies were analyzed to
define the patient populations. Frequency distribution of studies that reported the ICHD
clinical features as baseline characteristics of participants, and the means and standard
deviations of these features or percentage of participants demonstrating these reported
baseline characteristics were also described.
Results
Two hundred twenty nine studies met the selection criteria for this review (Figure 1). The list
of studies included in this review appears as Appendix C. Of these studies, 222 (96.9%) were
randomized controlled trials and 7 (3.1 %) were controlled clinical trials. Sample sizes ranged
from 11 to 1935 [mean (SD) 243.31 (336.30)] (Table 1), with a total of 48661 participants
across all studies. Migraine was the most studied headache type while cervicogenic headache
was the least studied. Most investigated pharmacologic interventions (n = 158, 69.0%). Non-
pharmacologic interventions (n = 71, 31.0%) included complementary and alternative
medicine (n = 29, 12.7%), psychotherapeutic intervention (n = 15, 6.6%), neurostimulation
and nerve blockade (n = 16, 7.0%).
Definition of study population and selection of participants in clinical trials
Two hundred ten studies (91.7%) used a classification system to define their study
populations, with 205 studies (89.5%) reporting adhering to the ICHD. One hundred twenty
seven studies (55.5%) diagnosed participants through interview, clinical examination and
diary entry (Table 2). It is unclear how diagnoses were arrived at or how the classification
system was used in the other 102 studies as these details were not provided.
Not all clinical features listed as ICHD diagnostic criteria for the headache types were
routinely specified among the inclusion criteria (Figure 2). For migraine studies, the most
75
commonly reported inclusion criteria was pain intensity (n = 123, 66.1%) and the least
common was pulsating quality of headache (n = 22, 11.8%). For tension-type headache
studies, the most commonly reported inclusion criteria were pain intensity (n = 21, 67.7%)
and frequency of attacks (n = 17, 54.8%) while the least common were bilateral location,
non-pulsating quality of headache and not affected by physical activity (all n = 7, 22.6%). For
cluster headache studies, the most commonly reported inclusion criteria were frequency of
attacks (n = 5, 71.4%) and severity, location and duration of headache (n = 4, 57.1%). For
cervicogenic headache studies, the most commonly reported inclusion criteria were pain
referred from the neck (n = 4, 80% of cervicogenic headache studies) and evidence of
cervical spine or muscle disorder (n = 3, 60% of cervicogenic headache studies). No
cervicogenic headache study specified improvement or resolution of pain in parallel with the
resolution of the neck disorder or lesion as an inclusion criterion.
Other inclusion criteria unrelated to the ICHD criteria but necessary to control for
potential confounders were frequently used in the headache studies. In general, participants
were included in studies if they belonged to a specific age group (mostly 18 to 65 years old),
were younger than 50 years old on their first headache attack, were experiencing a single
headache type or able to differentiate attacks according to headache types, were experiencing
headaches for at least 1 year, and had no comorbidities such as malignancy or depression.
Other selection criteria for study populations were related to the intervention investigated.
For example, many studies excluded participants who were pregnant or lactating, had taken
or were responsive to certain medications, or were taking other medications considered to be
prophylactic or contraindicated to the intervention.
Description of participants at baseline in terms of ICHD criteria
Not all clinical features listed as ICHD criteria for the headache types were routinely reported
76
as baseline characteristics of participants in the studies (Table 3). Nevertheless, among the
migraine studies that reported the baseline clinical features, the most reported characteristics
were severity of the headache (n = 64, 34.4%) and presence of photophobia and/or
photophobia (n = 44, 23.7%). Where reported, most participants demonstrated moderate to
severe pain intensity (92.5% of participants) and photophobia and/or phonophobia (79.4% of
participants) at baseline. For tension-type headache studies, the baseline headache
characteristic most reported was severity of the headache (n = 15, 46.9%). It was not possible
to pool severity data because different headache intensity scales were used. For cluster
headache studies, only two ICHD clinical features were reported as baseline characteristic of
participants: duration and frequency of attacks. Participants in the cluster headache studies
had about 3 attacks per day lasting for about an hour. For cervicogenic headache, the only
clinical feature reported as baseline characteristic of participants was abolition of headache
following nerve blockade (n = 1, 20%).
On further examination of the reported baseline characteristics of participants, there
was little to no information describing the extent to which participants demonstrated the
clinical features that were thought to least overlap with other headache types. For migraine
studies, nausea and/or vomiting, photophobia and phonophobia, and aggravation of the attack
by routine physical activity (8, 10) were reported in less than a quarter of the studies.
Similarly, the following features were not reported as baseline characteristics: headaches not
aggravated by routine physical activity for tension-type headache (8, 11, 12); presence of
autonomic symptoms for cluster headache (13); and pain, referred from the neck and
evidence of a cervical spine lesion for cervicogenic headache (2).
Discussion
This review reveals that the ICHD is routinely used to define study populations in headache
77
studies, suggesting consensus and endorsement among researchers of ICHD in providing a
framework for selecting participants. The use of a common framework such as the ICHD in
defining study populations, in turn, allows for better comparison and synthesis of data across
clinical trials. The methods of applying the ICHD criteria varied between studies, with most
conforming to the “gold standard” for diagnosing headaches of using the ICHD through
interview and physical examination (14).
Study populations across studies were homogenous beyond their headache features
because participants were also selected based on other criteria. These selection criteria, such
as being of a certain age at first headache episode and enrolment in the study, gender, health
status, medication use, and frequency of attacks, were apparently used to fit outcomes of
interest and to control for potential confounders. Whereas these selection criteria do not
reflect the validity of the diagnostic criteria used in the studies, they conform to guidelines for
clinical trials (15,16). The use of these guidelines in conjunction with the ICHD reflects how
well these tools complement each other in defining study populations. While study
populations were generally selected based on headache features listed in the ICHD, results of
this review did not make it possible to describe the extent to which these features were
demonstrated by participants at baseline. Few studies have provided this level of detail. Of
the ICHD features reported at baseline, the most reported were intensity, severity and
frequency of headaches. These headache features were consistent with some of the
recommended outcome measures for headache trials (15-18).
It is reasonable to think that not all headache features were reported as baseline
characteristics because the researchers of the studies already mentioned adhering to the ICHD
criteria in selecting the participants. Although selection criteria provide some information on
participant characteristics, further details on baseline headache characteristics may be helpful.
Because diagnosing using the ICHD is based on combinations of headache features, details
78
on which and to what extent headache features were demonstrated at baseline would clarify
participant features and potentially improve understanding and confidence in headache
classification in studies. Ultimately, such details may aid translation of research findings to
clinical populations.
Nevertheless, this large review presents a comprehensive snapshot of the landscape of
definitions of study populations in headache trials. The limitations of this review were that
we could not pool data for meta-analysis due to lack of standardization of outcome measures
used and we did not assess risk of bias within studies. However, these were redundant
because this review did not aim to evaluate treatment efficacy nor report pooled effect sizes
for treatment outcome. A step forward may be to explore the importance and impact of
reporting baseline headache characteristics of participants in headache trials.
In summary, study populations of treatment efficacy studies investigating migraine,
tension-type headache, cluster headache, and cervicogenic headache were generally defined
based on the ICHD criteria. It is unclear to what extent participants demonstrated the ICHD
criteria at baseline. This review provides a comprehensive snapshot of how study populations
are defined in headache trials. Results of this review also provide a starting point for
discussing the level of detail in reporting diagnostic headache features at baseline in clinical
trials.
79
Conflict of Interest Statement: All authors declare no conflicts of interest.
Acknowledgements:
This research received no specific grant from any funding agency in the public, commercial,
or not-for-profit sectors.
Maria-Eliza Aguila was supported by a fellowship through the Doctoral Studies Fund under
the Expanded Modernization Program of the University of the Philippines. Trudy Rebbeck
was supported by a fellowship from the Australian National Health and Medical Research
Council (NHMRC).
80
Article Highlights:
• Definitions of study populations in most treatment efficacy studies of frequent
recurrent headaches, namely, migraine, tension-type headache, cluster headache, and
cervicogenic headache strictly adhered to the International Classification of Headache
Disorders.
• It is unclear to what extent participants demonstrated the diagnostic criteria at baseline
as few studies provided this level of detail.
• Results of this review provide a starting point for discussing the level of detail in
reporting diagnostic headache features at baseline in clinical trials.
81
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J Am Osteopath Assoc 2005; 105: S16–22.
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for its recognition? Curr Pain Headache Rep 2006; 10: 454–8.
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migraine versus tension-type headache. Headache 2001; 41: 554–8.
13. Lai TH, Fuh JL, Wang SJ. Cranial autonomic symptoms in migraine: Characteristics
and comparison with cluster headache. J Neurol Neurosurg Psychiatry 2009; 80:
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in migraine: Third edition. A guide for investigators. Cephalalgia 2012; 32: 6–38.
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83
Figure Legends
Figure 1. Flow diagram of study selection
Figure 2. ICHD diagnostic criteria reported as inclusion criteria for study populations
84
Table Legends
Table 1. Characteristics of studies and participants in the review
Table 2. Process of diagnosing headaches used in clinical studies
Table 3. ICHD diagnostic criteria described among baseline characteristics of participants
with recurrent headache
85
Figure 1. Flow diagram of study selection
86
Figure 2. ICHD diagnostic criteria reported as inclusion criteria for study populations
87
Table 1. Characteristics of studies and participants in the review
Study characteristics
Design
RCT (n, %) 222 (96.9)
CCT (n, %) 7 (3.1)
Number of participants (mean, SD) 243.31 (336.30)
Headache classification studied [n (%) of total studies
reviewed]
Migraine 186 (81.2)
Tension-type headache 31 (13.5)
Cluster headache 7 (3.1)
Cervicogenic headache 5 (2.2)
Participant characteristics
% Female (mean, SD) 78.74 (17.88)
Age, years (mean, SD) 39.43 (0.48)
History of headaches, years (mean, SD) 11.2 (12.85)
88
Table 2. Process of diagnosing headaches used in clinical studies
Process of Diagnosis n (%) Studies
Use of classification system
Used a classification system 210 (91.7)
ICHD 205 (89.5)
Guidelines for controlled studies of drugs in 3 (1.3)
migraine by the International Headache
Society Clinical Trial Subcommittee
Silberstein-Lipton criteria for chronic migraine 2 (0.9)
Sjaastad criteria for cervicogenic headache 2 (0.9)
Did not report 19 (8.3)
Method of Diagnosis
Interview 81 (35.4)
Clinical examination 55 (24.0)
Diary 40 (17.5)
Diagnosed by health professional/s 26 (11.4)
Questionnaire 15 (6.6)
Diagnostic and laboratory tests 13 (5.7)
Self-identified 2 (0.9)
“Screening” 12 (5.2)
Did not report 102 (44.5)
89
Table 3. ICHD diagnostic criteria described among baseline characteristics of participants
with recurrent headache
ICHD Clinical Features n (%) Studies Mean (SD) of the

that Measured and Reported Headache
Reported the Feature Feature or
as Baseline % of Participants
Characteristic Demonstrating the
Feature at Baseline
A. MIGRAINE
Headache attacks lasting 4-72 hours (untreated or 29 (15.6) 21.31 (18.14) hours
unsuccessfully treated)
Unilateral location 11 (5.9) 59.8%
Pulsating quality 8 (4.3) 85.9%
Moderate or severe pain intensity 64 (34.4) 92.5%
Aggravation by or causing avoidance of routine 6 (3.2) 76.91
physical activity
Nausea and/or vomiting 36 (19.4) 52.4%
Photophobia and phonophobia 44 (23.7) 79.4%
At least 5 attacks
B. TENSION-TYPE HEADACHE
Headache occurring on ≥15 days/month on average 1 (3.1) 21 days
for >3 months (≥180 days/year)
Headache lasting from 30 minutes to 7 days 5 (15.6) 11.46 (4.89) hours
Bilateral location 0 (0)
Pressing/tightening (non-pulsating) quality 1 (3.1) 67%
Mild or moderate intensity 14 (45.2) 5.81 (1.70) (out of 10)
Not aggravated by routine physical activity such as 0 (0)
walking or climbing stairs
No nausea or vomiting (anorexia may occur) 1 (3.1) 100%
No more than one of photophobia or phonophobia 1 (3.1) 100%
90
ICHD Clinical Features n (%) Studies Mean (SD) of the
that Measured and Reported Headache
Reported the Feature Feature or
as Baseline % of Participants
Characteristic Demonstrating the
Feature at Baseline
C. CLUSTER HEADACHE
Severe or very severe unilateral orbital, supraorbital 3 (50) 82.75 (37.89) minutes
and/or temporal pain lasting 15-180
minutes if untreated
Conjunctival injection and/or lacrimation 0 (0)
Nasal congestion and/or rhinorrhoea 0 (0)
Eyelid oedema 0 (0)
Forehead and facial sweating 0 (0)
Forehead and facial flushing 0 (0)
Sensation of fullness in the ear 0 (0)
Miosis and/or ptosis 0 (0)
A sense of restlessness or agitation 0 (0)
Attacks have a frequency between one every other 1 (16.67) 3.33 (0.77) per day
day and 8 per day for more than half the
time when the disorder is active
D. CERVICOGENIC HEADACHE
Pain, referred from a source in the neck and 0 (0)
perceived in one or more regions of the
head and/or face
Clinical, laboratory and/or imaging evidence of a 0 (0)
disorder or lesion within the cervical spine
or soft tissues of the neck known to be, or
generally accepted as, a valid cause of
headache
Abolition of headache following diagnostic blockade 1 (20) 61.0 (5.4%)
of a cervical structure or its nerve supply
using placebo- or other adequate controls
Pain resolves within 3 months after successful 0 (0)
treatment of the causative disorder or lesion
91
CHAPTER THREE
Elevated Levels of GABA+ in Migraine Detected Using 1H-MRS
Chapter Three is the peer reviewed version of the following article: Aguila ME, Lagopoulos
J, Leaver AM, Rebbeck T, Hübscher M, Brennan PC, Refshauge KM. Elevated levels of
GABA+ in migraine detected using 1H-MRS. NMR Biomed. 2015; 28:890–7. doi:
10.1002/nbm.3321, which has been published in final form at
http://onlinelibrary.wiley.com/doi/10.1002/nbm.3321/full. This article may be used for non-
commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Supplementary methods and results on levels of excitatory and other brain chemicals in migraine
detected using proton magnetic resonance spectroscopy are presented in Appendix 3.

92
The study protocol for the study presented in this chapter appears as Appendix 4.
As co-authors ofthe paper “Elevated levels of GABA+ in migraine detected using 1H-MRS”,
we confirm that Maria Eliza Ruiz Aguila has madethe following contributions:
Signed: Jim Lagopoulos Date: 31March 2017
Signed: Andrew M Leaver Date: 31March 2017
Signed: Trudy Rebbeck Date: 31March 2017
Signed: Markus Hübscher Date: 31March 2017
Signed: Patrick C Brennan Date: 31March 2017
Signed: Kathryn M Refshauge Date: 31March 2017
93
ELEVATED LEVELS OF GABA+ IN MIGRAINE DETECTED USING PROTON
MAGNETIC RESONANCE SPECTROSCOPY
Maria-Eliza R. Aguilaa,b, Jim Lagopoulosc, Andrew M. Leavera, Trudy Rebbecka, Markus
Hübschera,d, Patrick C. Brennana, Kathryn M. Refshaugea
a
The University of Sydney Faculty of Health Sciences, 75 East Street, Lidcombe, New South
Wales 2141 Australia

b
University of the Philippines College of Allied Medical Professions, Pedro Gil Street,
Manila 1004 Philippines

c
Brain and Mind Research Institute, Sydney Medical School, 100 Mallett St, Camperdown,
New South Wales 2050 Australia

d
Neuroscience Research Australia and The University of New South Wales, Randwick,
NSW, Barker St, Randwick, New South Wales 2031 Australia
Maria-Eliza R. Aguila
[email protected]
Fax number: (+612) 9351 9601
Word count: 3133
94
Abstract Summary
Gamma-aminobutyric acid (GABA) has been implicated in several pain conditions
yet no study has systematically evaluated GABA levels in migraine using 1H-MRS. Accurate
detection, separation and quantification of GABA in people with migraine could elucidate the
role of this neurotransmitter in migraine pathophysiology. Such information may eventually
be useful in diagnosis and development of more effective treatment for migraine. The aims of
this study were therefore to compare the concentration of GABA+ in people with migraine
with asymptomatic individuals and to determine the diagnostic potential of GABA+ in
classifying people as having migraine or not.
In this case-control study, GABA+ levels in the brain were determined in 19
participants with migraine and 19 matched controls by 1H-MRS using MEGA-PRESS
sequence. The diagnostic accuracy of GABA+ for detecting migraine and the optimal cut-off
value were determined by receiver operating characteristic analysis.
GABA+ levels were significantly higher (P=0.002) in people with migraine [median
1.41 (interquartile range 1.31-1.50) institutional units] compared with controls [median 1.18
(interquartile range 1.12-1.35) institutional units]. GABA+ concentration appears to have
good accuracy in classifying individuals as having migraine or not [area under the curve
(95% CI) = 0.837 (0.71 – 0.96), P< 0.0001)]. The optimal GABA+ cut-off value for migraine
was 1.30 institutional units, with a sensitivity of 84.2%, specificity of 68.4% and positive
likelihood ratio of +2.67.
Outcomes of this study suggest altered GABA metabolism in migraine. These results
add to the scarce evidence on the putative role of GABA in migraine and provide basis to
further explore the causal relationship between GABA+ and the pathophysiology of migraine.
This study also demonstrates that GABA+ concentration has good diagnostic accuracy for
migraine. These findings offer new research and practice directions for migraine diagnosis.
95
Keywords
GABA, MRS, migraine disorders, ROC curve, sensitivity and specificity
Abbreviations
1
H-MRS = proton magnetic resonance spectroscopy
AUC = area under the curve
Cr = creatine
CSD = cortical spreading depression
CSF = cerebrospinal fluid
FWHM = full-width at half maximum
GABA = gamma-aminobutyric acid
GAD = glutamic acid decarboxylase
Glx = glutamate + glutamine
GM = grey matter
ICHD = International Classification of Headache Disorders
IQR = interquartile range
IU = institutional units
MEGA-PRESS = Mescher-Garwood point resolved spectroscopy
MP-RAGE = magnetization prepared – rapid acquisition gradient echo
ROC = receiver operating characteristic
TGVS = trigeminovascular system
WM = white matter
96
INTRODUCTION
Migraine is the third most prevalent disorder in the world and causes more than 22
million years of healthy life lost due to disability according to the 2010 Global Burden
of Disease Study (1). Despite its high prevalence, chronicity and consequent
disability, diagnosis of migraine is based on a set of signs and symptoms (2) that are
not specific to migraine (3), but overlap with other headache classifications. The lack
of specificity in migraine diagnosis is, in part, because diagnostic markers (4) related
to neurobiological mechanisms (5) are lacking. These uncertainties in diagnosis
impact on treatment of migraine, which many consider to be inadequate (6). It follows
that identification of specific diagnostic markers may improve understanding of the
neurobiological mechanisms of migraine and open new avenues for development of
effective therapeutics.
The pathophysiological events that are widely accepted as contributory to the
symptoms of migraine include cortical spreading depression (CSD)as well as
activation and sensitisation of the trigeminovascular system (TGVS) (5). CSD is
described as a wave of a brief, intense excitation of neurons and glial cells in the
central nervous system followed by a long, slowly propagating wave of inhibition (7,
8). The development of CSD triggers changes in cortical blood flow, featuring an
initial increase in cortical blood flow, followed by a period of reduced cortical blood
flow (9). CSD activates and sensitises the TGVS pain pathway, resulting in headache
(5).
Despite recent evidence supporting these pathophysiological bases for
migraine, the mechanisms of activation, propagation and termination of these events
remain unclear. One way to gain insight about the neurobiological mechanisms of
migraine is to investigate the role of excitatory and inhibitory neurotransmitters. It has
97
been hypothesised that an imbalance between excitatory and inhibitory mechanisms
results in the pathophysiological events leading to migraine (5, 10). Whilst the role of
excitatory neurotransmitters in migraine has been explored (11, 12), inhibitory
neurotransmission has received less attention. To date, only one other study has
reported in vivo concentrations of the inhibitory neurotransmitter, gamma-
aminobutyric acid (GABA), in people with migraine (13). Thus the role that GABA
assumes in the pathophysiology of migraine remains poorly understood.
GABA is widely distributed and is the most abundant inhibitory
neurotransmitter in the brain (14). Consequently, GABA has been implicated in
neuronal excitability and cortical functions such as modulation of pain (15).
Understanding the role of GABA in migraine is therefore important because
alterations in both neuronal excitability and pain processing constitute CSD and
TGVS activation and sensitisation in migraine (5).
Earlier investigations of GABA in migraine using indirect methods that
sampled saliva, cerebrospinal fluid (CSF) and blood have consistently reported
increased GABA levels. Increased salivary GABA has been reported during the ictal
period in people with migraine without aura, compared with headache-free periods,
and compared with non-migraine controls (16). Similar results were reported as early
as 1975 where elevated GABA levels were measured in the CSF during migraine
attacks and not present when the participants were free of migraine headaches (17).
Platelet GABA levels were found to be similar in people with migraine during
headache free periods and controls, but were not measured during migraine attacks
(18). Taken together, these studies suggest that GABA concentrations could be
increased in the brain in people with migraine.
98
Direct measures of GABA are now possible using proton magnetic resonance
spectroscopy (1H-MRS). Until recently, detecting GABA using 1H-MRS was difficult
due to spectral overlap between GABA and other neurometabolites (19), resulting in
large estimation errors. Recent technological advances now allow resolution of such
spectral overlaps using specialised sequences such as Mescher-Garwood point
resolved spectroscopy (MEGA-PRESS) (20). However, GABA resolved using such
editing techniques contain substantial macromolecule contamination and as such is
denoted as GABA+ and referred to as such in this study. The aims of this study were
to determine and compare GABA+ concentration detected by 1H-MRS using MEGA-
PRESS sequence in people with migraine and asymptomatic individuals and to
determine the diagnostic potential of GABA+ in classifying people as having
migraine or not.
MATERIALS AND METHODS
Design and outcome measure
In this cross-sectional case-control study, we compared GABA+ levels in the brainin
people with migraine with asymptomatic controls using 1H-MRS. To eliminate
possible confounding, the migraine and control groups were matched for age and
gender. Area under the receiver operating characteristic (ROC) curve, optimal cut-off
value, sensitivity, specificity, and positive likelihood ratio of concentration of
GABA+ for migraine were also determined. This research was granted ethics
approval by the Human Research Ethics Committee of the University of Sydney
(Protocol Number 15048).
99
Participant inclusion
Twenty participants with migraine were matched for age and gender with
asymptomatic controls. Participants were recruited through advertisements posted at
university, consumer support groups and primary care sites from 27 May to 15 August
2013. Participants were aged between 19 and 64 years.
Participants in the migraine group were included if they were diagnosed with
migraine by their attending neurologist/physician, fulfilled the International
Classification of Headache Disorders (ICHD)-II criteria for migraine (21), and had at
least one migraine attack per month. Participants in the control group were included if
they did not experience regular headaches and had no headache in the last three
months.
Participants in both groups were excluded if they: had non-migrainous
headaches according to ICHD-II criteria; had a history of neck injury, claustrophobia,
or severe depression (i.e., Depression Anxiety Stress Scales-21 score >21); were
pregnant; had conditions that would compromise spectroscopy data (e.g. implants,
tattoo, dental braces); or used medications known to alter GABA levels.
We conducted initial telephone screening of study volunteers to determine
eligibility. We then interviewed and physically examined all potential participants to
confirm classification according to ICHD-II criteria and to exclude those with non-
migrainous or mixed classification headache. Participants with migraine provided
information on history of migraine, frequency of episodes, typical location of
headache, and headache intensity in the last month and in the last 24 hours. All
participants provided written informed consent prior to participation.
100
Magnetic resonance spectroscopy data acquisition
Imaging was conducted at the Brain and Mind Research Institute imaging centre on a
3-Tesla GE Discovery MR750 scanner (GE Medical Systems, Milwaukee,
Wisconsin) using an 8-channel phased array head coil. The following images were
acquired in order: (a) three-dimensional sagittal whole-brain scout for orientation and
positioning of the subsequent 1H-MRS scans. To aid in the anatomical localisation of
sampled voxels, (b) a T1-weighted magnetization prepared – rapid acquisition
gradient echo (MP-RAGE) sequence producing 196 sagittal slices was acquired
(TR=7.2ms; TE=2.8ms; flip angle = 10°; matrix 256x256; 0.9mm isotropic voxels)
and (c) single voxel 1H-MRS using MEGA-PRESS acquisition (20)(TR=1800ms;
TE=68ms; NEX (phase cycling)=8; number of acquisitions=256; number of
points=4096; spectral width=5000; voxel size=3x3x3 cm3;total scan time=8:24)with
two chemical shift-selective imaging pulses for water suppression. Spectra were
shimmed to achieve full-width at half maximum (FWHM) of <13Hz. Anatomical
localisation of the voxel placement was based on the Talairach and Tournoux brain
atlas (22)and positioning was guided by the T1-weighted image.The centre of the
voxel was defined on the T1-weighted image on the midline sagittal plane
andpositioned at the posterior cingulate cortex in a location that encompassed
Brodmannareas 23 and 3. The superior-posterior most edge of the voxel extended into
the precuneus (Brodmannarea 7) and inferiorly into the retrosplenial cortex
(Brodmannarea 29 and 30). To cover asmuch grey matter (GM) as possible and
ensure the voxel did not encroach within the lateral ventricles or the splenium of the
corpus callosum, it was then rotated (in the sagittal plane) and translated to the left (in
the axial plane). The final position of the rotated voxel was lateral to the midline
101
posterior cingulate and posterior andsuperior to the splenium of the corpus callosum
(see Figure 1).

1
Following H-MRS acquisition, data were transferred offline for post
processing of GABA+ using the Gannet software toolkit (23) In brief the data were
first processed using the GannetLoad module which parses variables from the data
headers and applies a line broadening of 3 Hz. Next, individual spectra were
frequency- and phase-corrected using Spectral Registration (24). The data were then
processed by the GannetFit module, which employs a single Gaussian model to fit the
edited GABA+ signal and evaluates GABA+ concentration in institutional units (IU)
relative to water. The quality of the data was determined by the overall “Fit Error”
index of each subject. This index represents the standard deviation of the fitting
residual divided by the amplitude of the fitted peaks, and thus a measure of the signal-
to-noise ratio. Only spectra with a relative Fit Error of GABA+ below 10% were used
for the subsequent statistical analyses. There was no statistical difference between the
Fit Error, FWHM or the number of rejected shots between the two groups. Next, the
Tarquin software package was used to estimate glutamate + glutamine (Glx) from the
MEGA-edited spectra from edited on and off shots using the following parameters:
sampling frequency=5000; transmitter frequency=127MHz; data points=4096; water
cut off=45Hz; reference signal=H2O. Unsuppressed water data served as the internal
reference for all water scaling. Next, the coordinates of the acquisition voxels for each
participant were determined using the SAGE (Spectroscopy Analysis GE) software
package and the reconstructed acquisition voxels for all participants were corrected
for grey matter. GM correction was achieved by segmenting each participant’s
structural image into GM, white matter (WM) and CSF using the FAST4 algorithm as
implemented in FSL (25) and volume fractions were calculated. All statistical
102
analyses were conducted on GM-corrected GABA+. Finally, the radiographers,
neuroimaging expert who read the spectroscopy data and the neuroradiologist were
blinded to group allocation.
Statistical analyses
The calculated sample size (n=17 per group) was based on a hypothesised true mean
difference of 0.2 IU between groups and an estimated within group standard deviation
of 0.2 IU with a significance level of 0.05 with 80% power. Allowing for about 15%
attrition, we determined sample size to be 20 per group.
Descriptive statistics (median and interquartile range, IQR) were used to
report participant demographics and headache characteristics given the nonparametric
distribution of the data. GABA+ and Glx levels were compared between participants
with migraine and their matched asymptomatic controls using Wilcoxon Signed
Ranks Test. Pairs were excluded from analyses if either case or control data were
missing.
The ROC curve was drawn and the sensitivity, specificity and area under the
curve (AUC) were calculated to determine the diagnostic potential of GABA+ in
discriminating between people with migraine and controls. An AUC of 1 would
indicate that GABA+ correctly classifies all participants as having migraine or not,
and an AUC of 0.5 or less would indicate that GABA+ has no discriminatory value
(26). Interpretation of AUC varies and we used the following scale in interpreting the
discriminative ability of GABA+ for migraine: AUC greater than or equal to 0.90 as
excellent; AUC greater than or equal to 0.80 and less than 0.90 as good; AUC greater
than or equal to 0.70 and less than 0.80 as fair; and AUC of less than 0.70 as poor.
The optimal cut-off value for GABA+ was calculated by finding the minimum
103
distance on the ROC curve to the top of the y-axis, representing the point on the curve
closest to an ideal point where sensitivity and specificity are equal to one (27).
Positive likelihood ratio for the optimal cut-off value was calculated using the formula
sensitivity divided by one minus specificity.
Statistical analyses were conducted using Statistical Package for Social
Sciences® statistical software, version 21 (SPSS Inc., Chicago, Illinois, USA) for
Windows.
RESULTS
Participants
Twenty people with migraine and 20 age- and gender-matched controls participated in
this study. Figure 2 describes the flow of participants through the study and reasons
for exclusion of volunteers. Spectroscopy data were of sufficient quality to allow
analysis from 19 participants each from migraine and control groups.
Twenty eight (70%) participants were female. The median age and IQR were
31.5 and 28-47.2 years, respectively (Table 1). Participants with migraine reported, on
average, symptoms for more than 15 years and experienced approximately three
episodes in a month. Average headache intensity in the preceding month was rated
moderate to severe, and in the preceding 24 hours, rated none to moderate. No
participant in the migraine group had migraine-related symptoms on the day of
spectroscopy and none were taking GABAergic drugs for at least a month prior to
participation in the study (Table 1).
Outcomes
104
The concentration of GABA+ in participants with migraine was significantly higher
[median (IQR)] 1.41 (1.31-1.50) IU] than their age-matched controls [median (IQR)]
1.18 (1.12-1.35) IU]; P=0.002) (Figure 3). There was no difference in Glx between
migraine and control groups (P=0.313).
GABA+ concentration appears to have good accuracy for classifying
individuals as having migraine or not [AUC (95% confidence interval) = 0.837 (0.71
– 0.96), P<0.0001)] (Figure 4).
The optimal GABA+ cut-off value for the detection of migraine was 1.30 IU,
with sensitivity of 84·2%, specificity of 68·4% and positive likelihood ratio of +2.67
(Table 2).
Post-hoc analyses demonstrate no statistically significant correlation between
GABA+ concentration and age (correlation coefficient = -0.007, P = .950) and
headache severity (correlation coefficient = .313, P = 192), thus excluding these
variables as potential confounders.
DISCUSSION
This study is the first to provide direct evidence for the postulated role of GABA+ in
migraine pathophysiology. Utilising the MEGA-PRESS sequence specific for
resolving GABA+, we obtained accurate in vivo levels of GABA+ not previously
possible (20).In so doing, our results demonstrated higher concentration of GABA+ in
participants with migraine compared with their matched controls.
Our findings are consistent with previous work showing increased GABA
concentration in the human cerebral cortex during painful stimulation (15), and
corroborate earlier biochemical studies that suggested GABA levels may be increased
in the brain, based on indirect methods of measurement (16, 17). Further, our results
105
show that GABA+ levels are elevated during the interictal period. Our results differ
from those of an earlier study that reported no significant differences in GABA
concentration between people with migraine and controls (13). This difference in
findings is potentially because the spectroscopy technique we used was specific for
GABA+.
Results of post hoc analyses showing no statistically significant correlation
between GABA+ concentration and headache severity differ from an earlier report of
lower GABA levels in people with migraine with severe headaches(13). We think this
difference in findings may be explained by the lack of variability in headache
intensities of our participants (Table 1). Whether similar results would be obtained
from people with migraine with characteristics different from the participants of this
study remains to be investigated.
There are several methodological limitations associated with our study that
warrant further discussion. Firstly, the MEGA-PRESS technique, which we employed
to detect GABA, is not able to separate pure GABA from the macromolecule
component that arises from spins coupled at 3 and 1.7ppm. As such, the GABA+
signal we report needs to be interpreted with caution, as it is likely to have
macromolecule contamination. Next, the GABA+ signal in our study represents total
GABA within the acquired voxel and is derived from both intra- and extracellular
pools. This limits conclusions that can be made as to the relationship between the
GABA 1H-MRS signal and direct inhibitory processes. Further, we cannot explain the
cause or mechanism of increased GABA+ levels because of the cross-sectional design
of our study. However, the possibilities are that the increased GABA+ concentration
could be the result of a previous migraine attack, a characteristic brain state prior to an
attack or a feature of the “migraine brain” that initiates an attack. Of these, we
106
speculate that the increased GABA+ level in migraine contributes to the initiation or
propagation of symptoms of migraine. This supposition is based on recent evidence
that GABA causes vasodilation during the interaction between neurons, blood vessels
and astrocytes during CSD and TGVS activation (9, 28, 29). We further propose that
the increased GABA+ level is linked with the hypothesised altered excitability of
cortical neurons during the interictal period (30). This is consistent with suggestions
of increased GABA resulting from neurogenic inflammation (31), as is believed to
occur in migraine. Finally, data on the consumption of substances that may affect
GABA concentrations such as nicotine (cigarette), alcohol and caffeine were not
collected.
Potential explanations for the increased GABA+ concentration could be an
increase in the number of GABAergic neurons, changes in intracellular (e.g. increased
pre-synaptic GABA due to changes in GABA synthesis or receptor expression,
degradation or reuptake) or extracellular GABA levels (15, 32). Of these possibilities,
we propose that the increased GABA+ level is due to an increase in intracellular
GABA synthesis resulting from an altered function of its synthesising enzyme,
glutamic acid decarboxylase (GAD) (33). This enzyme appears to be expressed only
in GABAergic neurons and therefore is a good marker for neurons that use GABA as
a neurotransmitter.
Results of ROC curve analysis demonstrate that GABA+ has good predictive
ability for migraine, identifying people with GABA+ concentrations equal to or
greater than 1.30IU as having migraine. These findings indicate the utility of GABA+
as a potential biomarker for migraine and are likely to contribute to more specific
migraine diagnosis and possibly even targeted and individualised treatment. At
present, no biomarker for migraine has been systematically validated (4). Further
107
research could determine the validity of GABA+ in discriminating between people
with migraine, other headache types and controls. The cut-off value calculated from
this study may be used in further investigations aimed at identifying objective
diagnostic biomarkers for migraine.
This study provides new information on altered GABA+ in migraine and
contributes to clarifying the neurobiological mechanisms of migraine. GABA has
been previously shown to cause vasodilation during neurovascular coupling (29), as in
that which occurs during CSD and TGVS activation (9).Given the link between
GABA and the generally accepted theories of migraine pathophysiology, evidence
from this study indicates that GABA+ could be a candidate diagnostic marker for
migraine. Future research could also include investigations on the mechanisms
causing the increased GABA+ in migraine through randomised controlled trials of
drugs targeting GAD and on the nociceptive function of the increased GABA through
longitudinal studies.
CONCLUSIONS
Our results demonstrate altered GABA+ metabolism in migraine when measured
using magnetic resonance sequences specifically tailored to resolve GABA+. Our
study thus adds to the scarce evidence on the putative role of GABA in migraine and
provides basis to further explore the causal relationship between GABA+ and the
pathophysiology of migraine. Results of this study also suggest good diagnostic
accuracy for GABA+ for migraine and offer new research directions for migraine
diagnosis.
108
Acknowledgements
We thank all the participants for their cooperation and the staff of the Southern
Radiology Group at the Brain and Mind Research Institute for their support during the
conduct of this study.
Funding
This research was funded by a Bridging Grant from the University of Sydney. Maria-
Eliza Aguila was supported by a fellowship through the Doctoral Studies Fund under
the Expanded Modernization Program of the University of the Philippines. Trudy
Rebbeck was supported by a fellowship from the Australian National Health and
Medical Research Council (NHMRC). Markus Hübscher was supported by a
postdoctoral fellowship from the German Academic Exchange Service (DAAD).
Conflict of interest statements
All authors report no disclosures.
109
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Table 1.Characteristics of participants (n =40)
PARTICIPANT CHARACTERISTICS GROUP
MIGRAINE CONTROL
(n=20) (n=20)
Demographic characteristics
Age [median (IQR)] (years) 33 (28.25-47.25) 30 (26.5 – 47.5)
Gender (female) [n(%)} 14 (70) 14 (70)
Headache Characteristics
History of migraine [median (IQRa)] (months since first 180 (60-288)
episode)
Frequency of headache in a month [median (IQR)] (n) 2.75 (1.5-8.5)
Episode duration [median (IQR)] (hours) 48 (24-48)
Average headache intensity last month [median (IQR)] (0-10) b 6 (6-8)
Average headache intensity last 24 hours [median (IQR)] (0- 1.5 (0-6)
10)b
Migraine Medications
Non-steroidal anti-inflammatory drugs (number of participants) 6
(n)
Triptans (number of participants) (n) 4
Paracetamol (number of participants) (n) 4
Beta blockers (number of participants) (n) 2
Selective serotonin reuptake inhibitor (number of participants) 1
(n)
a
IQR = interquartile range
b
Headache intensity: Numerical rating scale 0-10; 0=no pain, 10 = worst possible pain
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Table 2. Distribution of GABA+ values in migraine (n=20) and control groups (n
=20)
Migraine group Control group
GABA+ > 1.3IUa 16 6
GABA+ < 1.3IU 3 13
Missing data 1 1
a
IU = institutional units
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Figure Legends
Figure 1. Fitted GABA+ resolved data using MEGA-PRESS. (A) Raw GABA edited
spectrum highlighting GABA+, Glx signals. (B) Modelled data (red), raw
GABA+ signal (blue) and residuals (black) exemplifying the accuracy of
the data fit. (C) Representative water data [inset: unedited raw data at
3.0ppm highlighting creatine (Cr) and choline peaks]. (D) T1-weighted
structural image showing the anatomical localisation of 3x3x3
cm3acquisition voxel. (E) Processed GABA+-edited difference spectrum
before (green) and after (blue) frequency and phase correction. (F) Cr
signal over the duration of the experiment. The y-axis represents the
frequency (in ppm) of the Cr signal and shows that there is negligible drift
over this period.
Figure 2. Flow of participants through the study.
Figure 3.Concentration of GABA+ in participants with migraine and asymptomatic
controls. Data are presented as box plots, where the boxes represent values
between the 25th and 75th percentiles (interquartile range, IQR), the line
within the box, the median, and the bars outside the box (whiskers), the
range of data. Outliers are plotted as circles (1.5×IQR or more below the
25th or above the 75th percentile) and stars (3×IQR or more below the
25th or above the 75th percentile).
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Figure 4. Receiver operating characteristic curve evaluating GABA+ in people with
migraine and controls. Area under the curve = 0.837 (95% confidence
interval 0.71-0.96), P< 0.0001
119
Figure 1.Fitted GABA+ resolved data using MEGA-PRESS. (A) Raw GABA edited
spectrum highlighting GABA+, Glx signals. (B) Modelled data (red), raw
GABA+ signal (blue) and residuals (black) exemplifying the accuracy of the data
fit. (C) Representative water data [inset: unedited raw data at 3.0 ppm highlighting
creatine (Cr) and choline peaks]. (D) T1-weighted structural image showing the
anatomical localisation of 3 x 3 x 3 cm3 acquisition voxel. (E) Processed GABA+-
edited difference spectrum before (green) and after (blue) frequency and phase
correction. (F) Cr signal over the duration of the experiment. The y-axis represents
the frequency (in ppm) of the Cr signal and shows that there is negligible drift
over this period.
120
Figure 2.Flow of participants through the study.
121
Figure 3.Concentration of GABA+ in participants with migraine and asymptomatic controls.
Data are presented as box plots, where the boxes represent values between the
25th and 75th percentiles (interquartile range, IQR), the line within the box, the
median, and the bars outside the box (whiskers), the range of data. Outliers are
plotted as circles (1.5×IQR or more below the 25th or above the 75th percentile)
and stars (3×IQR or more below the 25th or above the 75th percentile).
122
Figure 4.Receiver operating characteristic curve evaluating GABA+ in people with migraine
and controls. Area under the curve = 0.837 (95% confidence interval 0.71-0.96),
P< 0.0001
123
CHAPTER FOUR
The Association Between Clinical Characteristics of Migraine and
Brain GABA Levels: An Exploratory Study
Chapter Four is the peer reviewed version of the following article: Aguila ME, Rebbeck T,
Leaver AM, Lagopoulos J, Brennan PC, Hübscher M, ,Refshauge KM. The association
between clinical characteristics of migraine and brain GABA levels: An exploratory
study.JPain.2016; 17:1058–67.doi:10.1016/j.jpain.2016.06.008, which has been published in
final form at http://www.jpain.org/article/S1526-5900(16)30109-2/fulltext; with permission
from the American Pain Society.
124
As co-authors ofthe paper “The association between clinical characteristics of migraine and
brain GABA levels: An exploratory study”, we confirm that Maria Eliza Ruiz Aguila has
madethe following contributions:
Signed: Jim Lagopoulos Date: 31 March 2017
Signed: Patrick C Brennan Date: 31 March 2017
Signed: Markus Hübscher Date: 31 March 2017
Signed: Kathryn M Refshauge Date: 31 March 2017
125
THE ASSOCIATION BETWEEN CLINICAL CHARACTERISTICS OF MIGRAINE AND
BRAIN GABA LEVELS: AN EXPLORATORY STUDY
Maria-Eliza R. Aguila, MPhysioa,b, Trudy Rebbeck, PhDa, Andrew M. Leaver, PhDa, Jim
Lagopoulos, PhDc, Patrick C. Brennan, PhDa, Markus Hübscher, PhDa,d, Kathryn M.
Refshauge, PhDa
a

b

c
Brain and Mind Centre, Sydney Medical School, 100 Mallett St, Camperdown, New South

d
Corresponding Author
Maria-Eliza Ruiz Aguila, MPhysio
Fax number: (+612) 9351 9601
Email address: [email protected]
Disclosures
This research was funded by a Bridging Grant from the University of Sydney. Maria-Eliza
Aguila was supported by a fellowship through the Doctoral Studies Fund under the Expanded
Modernization Program of the University of the Philippines. Trudy Rebbeck was supported
126
by a fellowship from the Australian National Health and Medical Research Council
(NHMRC). Markus Hübscher was supported by a postdoctoral fellowship from the German
Academic Exchange Service (DAAD).
All authors declare no conflicts of interest.
127
THE ASSOCIATION BETWEEN CLINICAL CHARACTERISTICS OF MIGRAINE AND
BRAIN GABA LEVELS: AN EXPLORATORY STUDY
Maria-Eliza R. Aguila, MPhysioa,b, Trudy Rebbeck, PhDa, Andrew M. Leaver, PhDa, Jim
Lagopoulos, PhDc, Patrick C. Brennan, PhDa, Markus Hübscher, PhDa,d, Kathryn M.
Refshauge, PhDa
a

b

c
Brain and Mind Centre, Sydney Medical School, 100 Mallett St, Camperdown, New South

d
Abstract
Migraine is prevalent and disabling yet is poorly understood. One way to better understand
migraine is to examine its clinical characteristics and potential biomarkers such as gamma-
aminobutyric acid (GABA). The primary objective of this study was to explore whether
relevant disease characteristics of migraine are associated with brain GABA levels. Twenty
adults fulfilling the established diagnostic criteria for migraine and 20 age- and gender-
matched controls completed this cross-sectional study. Pain, central sensitization, negative
emotional state, and perceived disability were measured using Short-form McGill Pain
Questionnaire-2, Central Sensitization Inventory, Depression Anxiety Stress Scales-21, and
Headache Impact Test-6, respectively. Secondary analysis of brain GABA levels of the same
128
cohort measured using proton magnetic resonance spectroscopy was conducted. The migraine
group had significantly higher scores on pain, central sensitization and disability than the
control group. Correlation analyses showed fair positive association between GABA levels
and pain and central sensitization scores. No association was found between GABA levels
and emotional state and disability. These findings are preliminary evidence supporting the
use of questionnaires and GABA levels in characterizing migraine better and broadening the
diagnostic process. These findings also strengthen the rationale for the role of GABA in
migraine pathophysiology and corroborate the potential of GABA as a migraine biomarker.
Perspective
Higher pain and central sensitization scores were associated with increased brain GABA
levels in individuals with migraine. These findings offer preliminary evidence for the
usefulness of measuring pain and central sensitization in migraine and provide some support
for the possible role of GABA in migraine pathophysiology and its potential as a diagnostic
marker.
Key Words
GABA, migraine disorders, headache, central sensitization, disability, questionnaires
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Introduction
Migraine is among the most prevalent and disabling chronic conditions globally [43].
Despite the burden that migraine imposes on the individual and society [26,27], its
underlying mechanisms remain poorly understood. Consequently, migraine diagnosis is
nonspecific [44] and its treatment may be inadequate [41]. A better understanding of
migraine, and ultimately its diagnosis and treatment, may be gained by deeper investigation
of characteristic clinical features and their relationship with potential biomarkers.
One possible biomarker for migraine is gamma-aminobutyric acid (GABA). GABA is
the predominant inhibitory neurotransmitter in the central nervous system [13] and is an
important regulator of the balance between excitation and inhibition in the brain [30]. As
such, GABA has been implicated in clinical conditions thought to involve an imbalance
between excitatory and inhibitory processes. Interestingly, recent studies have also implied
that GABA mediates excitatory actions as well, for example in the development of epilepsy
[45]. We have recently published findings that brain GABA levels are significantly higher in
people with migraine compared to age- and gender-matched controls and have demonstrated
that GABA has good diagnostic potential for migraine [1]. These findings were the first
direct evidence for the putative role of GABA in migraine and its potential as a migraine
biomarker. Following the three-stage model suggested by Hlatky and colleagues [22] to
validate biomarkers, it is then necessary to establish migraine characteristics associated with
GABA and finally to determine that screening using the biomarker leads to targeted treatment
and eventually reduces disease burden. The second stage of validation might be furthered by
exploring associations of GABA levels with important clinical characteristics.
Four important clinical characteristics of migraine are pain, central sensitization,
negative emotional state and disability. Pain is important in migraine diagnosis to an extent
that pain characteristics help distinguish migraine from other headache types [19,20].
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Headache pain that is moderate to severe, throbbing and unilateral is characteristic of
migraine [20]. Central nervous system sensitization involves decreased pain thresholds and
exaggerated responses to noxious and nonnoxious stimuli [9]. Sensitization is commonly
manifested in migraine as hyperalgesia [10] and cutaneous allodynia [9] such as pain when
combing the hair, exposed to heat or cold, or wearing eyeglasses [28]. Symptoms of negative
emotional states such as depression, stress and anxiety have been reported to be more
frequent in people with migraine compared to controls [8,46] and associated with the
tendency to perceive normal bodily sensations as disturbing [46]. Level of disability based
on scores on self-report questionnaires has been consistently reported to be higher in people
with migraine than people with other headache types [e.g. 33,40] and those without
headaches [24]. An example of disability which differentiates migraine from other headache
types is the avoidance of physical activity or reported aggravation of symptoms by routine
physical activity during a migraine episode [19,20].
It is possible that pain, central nervous sensitization, emotional state, and disability
are associated with GABA levels in migraine. First, pain has been shown to be modulated by
GABA [13] and therefore any change in pain may be associated with changes in GABA
levels. Second, central nervous system sensitization in migraine is theoretically linked with
GABA levels considering one proposed pathophysiological mechanism for migraine. It has
been hypothesized that a cortical excitatory – inhibitory imbalance in migraine leads to
headache and other symptoms [42]. GABA may have a putative role in this imbalance.
Third, symptoms of emotional states have been shown to involve the GABA system. There
is abundant evidence from human and animal studies that anxiety and depression are
associated with reduced GABAergic function, yet recent animal studies indicate that
symptoms of depression reduce when GABA action through GABA-B receptors is blocked
[32]. Fourth, disability in migraine may be viewed as a manifestation of dysregulation in
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brain and/or body systems that may have developed in the course of repeated migraine
episodes [4]. GABA is a potential mediator in this dysregulation, given its role in regulating
excitatory-inhibitory balance in the brain [30]. The potential relationships between GABA
levels and central nervous sensitization, emotional state, and disability have not been
investigated in migraine.
The primary aim of this study was to explore whether relevant clinical characteristics
of migraine including pain, central nervous system sensitization, emotional state and
headache-related disability are associated with brain GABA levels. A secondary aim of this
study was to compare clinical characteristics, particularly central nervous sensitization and
emotional state, between people with migraine and asymptomatic controls. By exploring the
relationship of clinical characteristics with GABA levels, we aim to build on the process of
validating GABA as a migraine biomarker, inform migraine diagnosis and better understand
migraine.
Methods
Design
A secondary analysis of a previous cross-sectional case-control study that compared
GABA levels between people with migraine and age-and gender-matched controls [1] was
performed to explore the association between GABA levels and migraine clinical
characteristics. This research was granted ethics approval by the Human Research Ethics
Committee of the University of Sydney (Project Number 2012/581).
Participants
Participants with migraine were eligible for the original study if they were diagnosed
with migraine by their attending neurologist/physician and if their headache features fulfilled
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the International Classification of Headache Disorders (ICHD)-II criteria for migraine [19].
Participants in the control group were included if they did not experience recurrent
headaches, had never experienced a migraine episode, and were not experiencing significant
pain nor pain longer than 3 months at the time of the study. Participants in the control group
were matched to the migraine group for age and gender. Participants in both groups were
excluded if they used medications known to alter GABA levels. Complete inclusion and
exclusion criteria and other details of participant recruitment are described elsewhere [1]. In
brief, participants were recruited through advertisements posted at university, consumer
support groups and primary care sites.
Procedures
We conducted initial telephone screening of potential participants to determine their
eligibility. All participants in the migraine group then underwent an interview and physical
examination to confirm classification according to ICHD-II criteria and to exclude headache
participants with non-migrainous or mixed classification headache. Controls were also
interviewed and physically examined.
Participants with migraine provided information on headache characteristics including
history of migraine, frequency of episodes, typical duration of each migraine episode, and
headache intensity in the last month using the visual analogue scale (VAS: with anchors at 0
and 10: 0 = no pain, 10 = worst pain possible). In addition, participants described the location
of their headache, associated symptoms, and any medication and/or treatment received.
All participants satisfying the inclusion and exclusion criteria completed self-
administered paper-and-pen questionnaires that were arranged in a standardized manner to
ensure consistency. Questionnaires, described below, included information about pain and
central nervous system sensitization experience, emotional state, and disability. Completed
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questionnaires were checked for any misunderstood or inadvertently missed item.
Participants then underwent proton magnetic resonance spectroscopy to determine brain
GABA levels. All participants provided written informed consent prior to participation.
Outcomes
Brain GABA Levels
Brain GABA levels were measured in institutional units by single-voxel proton magnetic
resonance spectroscopy using the Mescher-Garwood point resolved spectroscopy sequence
(TR = 1800 ms; TE = 68 ms; number of excitations (phase cycling), 8; number of
acquisitions, 256; number of points, 4096; spectral width, 5000; voxel size, 3 × 3 × 3 cm3;
total scan time, 8 min 24 s). The voxel was positioned lateral to the midline posterior
cingulate, and posterior and superior to the splenium of the corpus callosum (Figure 1).
Spectroscopy was performed during the interictal period for participants in the migraine
group; no one had migraine-related symptoms on the day of testing. Details of the full
spectroscopy methods and parameters are reported elsewhere [1].
Clinical Characteristics Based on Self-Report Questionnaires
Migraine pain characteristics were described using the Short-form McGill Pain
Questionnaire-2 (SF-MPQ-2) comprising 22 pain quality descriptors scored for intensity on a
0 to 10 Likert scale. SF-MPQ-2 has been validated for use for neuropathic pain [12], as is
thought to be present in migraine [3]. For this study, the top and bottom quartiles of intensity
scores were considered to reflect the words that people with migraine used the most and least,
respectively, to describe their headache. SF-MPQ-2 also provided information on the
multidimensional nature of the migraine pain experience by generating summary scores for
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continuous, intermittent, neuropathic and affective pain subscales, aside from the total SF-
MPQ-2 scores.
Presence of symptoms of central nervous system sensitization was measured using the
Central Sensitization Inventory (CSI) [31]. The CSI is a highly reliable and valid screening
tool for central sensitivity syndromes (CSS), that is, diseases that have central sensitization as
a common feature [34]. Scores of >40 indicate possible CSS, with higher CSI scores
reflecting a higher degree of sensitization. CSI discriminates people with central sensitivity
syndromes, including migraine, from those without pain, with a sensitivity = 81%; specificity
= 75% [34] and from those with chronic pain without central sensitivity symptoms
(sensitivity = 83%; specificity = 55%) [35].
Emotional state was measured using the Depression Anxiety Stress Scales-21 (DASS-
21) [29]. The DASS-21 is a short, valid and highly reliable instrument providing depression,
anxiety and stress scores based on frequency and severity of symptoms [21]. It has been used
to investigate the association of negative emotional state with migraine [6,18,36].
Perceived levels of disability were measured using the Headache Impact Test-6TM
(HIT-6), a brief questionnaire on the impact of the headache on work and daily activities
[25]. The HIT-6 was shown to have high reliability and good validity in discriminating
migraine from other headaches [25].
Statistical Analyses
Spearman’s rho and Kendall’s tau correlations were used to explore associations
between GABA levels and normally and non-normally distributed clinical characteristics,
respectively, in individuals with migraine. Correlation coefficients were interpreted as
follows: greater than.75, good to excellent relationship; 0.50 to 0.75, moderate to good
relationship; 0.25 to 0.50, fair relationship; and 0.00 to 0.25, little or no relationship [39].
135
These correlation analyses were performed after normality of the distribution of data was
tested using the Shapiro-Wilk statistic.
We conducted area under the receiver operating characteristic (ROC) curve analysis
for clinical characteristics that had at least a fair association with GABA levels and that might
be useful in discriminating migraine. To this end, we computed for optimal cut-off value,
area under the curve, sensitivity, and specificity of the questionnaire score. Based on these
calculations, we interpreted diagnostic accuracy to be excellent, good, fair or poor [47].
Descriptive statistics (frequency, mean and standard deviation, SD, median and
interquartile range, IQR) of headache characteristics and self-report questionnaire scores
were used to report clinical characteristics. The Wilcoxon signed rank test was used to
determine differences in clinical characteristics based on questionnaire scores between
migraine and control groups given that not all were normally distributed. Pairs were excluded
from analysis if either case or control data were missing. Glass’s  was calculated to
compare the difference between mean scores of the migraine and control groups.
Statistical analyses were conducted using Statistical Package for Social Sciences®
statistical software, version 21 (SPSS Inc., Chicago, Illinois, USA) for Windows.
Significance level was set at 0.05.
As this was an exploratory study using secondary analysis of brain GABA levels from
a previous cross-sectional case-control study [1], the sample size of this present study was
based on that of the previous study (n = 40). This sample size was powered to detect group
differences in brain GABA levels.
Results
Participants
136
Twenty people with migraine and 20 age- and gender-matched controls participated in
this study. The median age (IQR) of the migraine group was 33 (28–47) years while the
median age of the control group was 30 (26–48) years. Fourteen out of 20 (70%) participants
of each group were female. The average duration of migraine symptoms was 15 years, with a
frequency of three to five times per month (Table 1). Migraine characteristics of the
participants (Table 1) were consistent with the ICHD diagnostic criteria for migraine. Most
participants reported more than one location of headache, with 85% reporting temporal
location and 80% reporting frontal location (Figure 2).
Participants most commonly chose aching (95%), tiring-exhausting (80%), throbbing
(75%), sickening (70%), and sharp (65%) from the SF-MPQ-2 to describe their headaches
(Figure 3). More than half the participants with migraine (55%) were not taking migraine
medications at the time of assessment and had neither sought physical treatment such as
physiotherapy nor alternative treatment such as acupuncture (Table 1).
Of all the variables considered, only the following variables were normally
distributed: history of migraine, intensity of headache in the last month, and scores on HIT-6,
CSI, MPQ-continuous, MPQ-affective, and MPQ Total scores.
Association between Clinical Characteristics and GABA Levels among People with
Migraine
There was fair positive association between GABA levels and pain scores,
specifically total SF-MPQ-2 scores (ρ = .47, P = 0.04) and SF-MPQ-2 scores on intermittent
(τ = .33, P = 0.04), neuropathic (τ = .37, P = 0.03) and affective (ρ = .49, P = 0.03) pain
subscales (Table 2 and, Figure 4A). There was also fair positive association between GABA
levels and scores on the CSI (ρ = .48, P = 0.03) (Figure 4B). GABA levels were not
associated with headache history, frequency, duration or intensity, continuous pain domain
137
on MPQ, depression, anxiety and stress scales of DASS-21, nor levels of disability (P > 0.05;
Table 2).
Of those variables having fair association with GABA levels, only CSI scores were
suitable for ROC analysis because both migraine and control groups had scores greater than 0
on the CSI. Results of this analysis revealed that CSI appears to have good accuracy for
classifying individuals as having migraine or not [AUC (95% confidence interval) = 0.88
(0.76-1.00), P <0.001)] (Figure 5). The optimal CSI cut-off score to distinguish people with
migraine from those who do not get regular headaches was 22.5, with sensitivity of 95%,
specificity of 80% and positive likelihood ratio of +4.75.
Clinical Characteristics of Migraine and Control Groups Based on Self-Report
Questionnaires
There were significant differences between groups for scores on all of the self-report
questionnaires (Table 3). The two groups differed the most in their scores on HIT-6 scores,
SF-MPQ-2 continuous pain and CSI, as shown by their respective Glass’s . Notably, there
was no statistically significant between-group difference for the anxiety scale of DASS-21.
Participants from both groups had scores categorized as “normal” for this scale.
Discussion
Our results show that pain and central sensitization scores had a fair positive
association with GABA levels in migraine. These results support a putative role for GABA in
migraine pathophysiology particularly where migraine presents with moderate to severe
headache and central nervous system sensitization. This association between these migraine
features and GABA also provides some further support in validating GABA as a potential
biomarker for migraine.
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GABA levels were associated with three of the four summary scales of pain quality
and severity contained in the SF-MPQ-2, namely intermittent, neuropathic and affective pain.
People with higher pain scores on SF-MPQ-2 scores tended to have higher GABA levels.
These results give rise to the question whether the observed relationship between GABA
levels and pain scores are characteristic of migraine or of any pain condition. We believe that
the association between increased GABA levels and higher pain scores indicates a change in
brain chemistry specific to migraine or chronic episodic headache for three reasons. First, we
measured GABA levels during the interictal period, when participants were free of headache.
Second, two participants in the control group had mild pain in the limb. Third, increased
GABA levels in migraine oppose the decreased GABA levels reported in other pain
conditions from previous studies, although measured from different brain regions (from the
insula in fibromyalgia [15] and thalamus in people with spinal cord injury with neuropathic
pain compared to those without neuropathic pain [17]. The association between GABA levels
and pain scores also implies that SF-MPQ-2 may be used as a basis for
inferring about GABA levels when spectroscopy data are unavailable. Interestingly, GABA
levels were not associated with headache intensity based on participant rating of their usual
headaches. We speculate that the difference in findings is because participants considered
pain differently when presented with words on the SF-MPQ-2 than when asked to rate their
usual headaches. Using the SF-MPQ-2, participants rated the intensity associated with the
specific words. On the other hand, when asked to rate the intensity of their usual headaches,
participants could be thinking of the whole headache experience, how the headache affected
their lives or how long they had been dealing with the symptoms.
Increased GABA levels were associated with higher central sensitization scores. This
means that increased GABA levels are most likely to be higher when central sensitization
symptoms are more frequent. One possible explanation for this relationship may be the role
139
of GABA in regulating excitatory-inhibitory balance in the brain [30]. The increased GABA
levels in migraine may cause abnormal excitability of the trigeminovascular system, as
previously postulated for migraine [1,42]. This explanation is plausible given that most of the
participants reported having photophobia and/or phonophobia, both considered clinical
expressions of sensitization [7,10,42]. We have previously reported that glutamate +
glutamine measured from the same cohort did not differ between the migraine and control
groups [1]. These findings support the role of increased GABA in the altered excitability of
the brain. Another possible explanation for the relationship between increased GABA levels
and higher sensitization is based on the role of GABA in neurovascular coupling. GABA has
been shown previously to cause vasodilation during neurovascular coupling [23] where
cortical blood flow adjusts according to cortical activity. Neurovascular coupling may be
impaired in migraine, leading to the progression of migraine symptoms. Therefore the
relationship between increased GABA levels and higher central sensitization scores may also
be indicative of a role for GABA in migraine symptoms. Further, results of ROC curve
analysis indicate that people with CSI scores > 22.5 are nearly five times more likely to have
migraine than those with scores below this. This cutoff score is lower than the previously
reported CSI cutoff score of 40 to identify central sensitization syndromes [34,35], suggesting
the possible specific use of the CSI for migraine identification. The CSI provides information
beyond ICHD criteria and therefore broadens the diagnostic process and enhances the
clinician’s appreciation of the patient’s experience.
GABA levels were not associated with headache characteristics, emotional state and
perceived disability in this cohort. Our results differ from a previous report showing lower
GABA levels in more severe headache [2]. The lack of association in this present study may
be due to the timing of our GABA measurement (interictal period) and also possibly because
140
our participants were more homogenous with generally more frequent and more severe
headaches than the cohort reported on by Bigal and colleagues [2].
The homogeneity of headache characteristics of the migraine cohort was ideal for
investigating potential disease biomarkers [38] and therefore was one of the strengths of this
study. We also believe that we were able to detect an association between GABA and pain
and central sensitization partly because GABA levels were measured from the cingulate
cortex, previously shown to have altered functioning in pain states [14]. Localizing the voxel
in this region also allowed the use of a large voxel to maximize signal-to-noise ratio for
GABA [1].
Although this study provides new insights on migraine characterization and the role of
GABA in pathophysiology, some limitations should be considered. First, GABA levels were
measured from just one region to achieve good signal quality in a short acquisition time. We
do not know if increased GABA levels, and therefore their association with clinical
characteristics, are different in other brain regions. Second, spectroscopy was done during the
interictal period so it is not possible to tell if GABA levels are also increased during the ictal
period. It seems reasonable to speculate, however, that GABA levels might also be altered if
measured during the ictal period. This speculation is based on a previous proposal that the
brain in migraine changes in function and structure over time due to repeated migraine
episodes [4]. These changes may include a dysregulation of the excitatory-inhibitory balance
in the brain involving GABA. Correspondingly, we speculate that GABA levels measured
during the ictal period might also be associated with symptoms of central sensitization and
pain. Third, this study was intended to be exploratory and therefore was not set up for
multivariate analyses and adjustment for multiple comparisons. For the same reason, we did
not design the study to include the presence or absence of aura symptoms nor the varied
141
medications of the participants as covariates in the analyses. Lastly, DASS-21 and HIT-6
scores of our participants had insufficient variability for rigorous analysis.
Further studies are therefore required to confirm the results of our study. Larger,
longitudinal cohort studies may investigate the association between GABA levels and clinical
characteristics in migraine and other headache types during the ictal and interictal periods.
Additional factors that may be related with GABA levels in migraine may be investigated
such as other neurotransmitters, presence or absence of aura, and medications. Similarly, it
will be useful to determine whether questionnaires can differentiate migraine from other
headache types. Further studies can also build on results of this study to validate GABA as a
biomarker and address the lack of established biomarkers for migraine [11].
Nevertheless, results of this study strengthen the rationale for the role of GABA in
migraine pathophysiology and thus add to the understanding of migraine. The association of
pain and central nervous system sensitization symptoms with GABA levels in migraine
suggests that patients’ subjective reports correlate with brain chemistry. Hence assessing
these clinical characteristics using SF-MPQ-2 and CSI is useful, allows more specific
characterization of migraine. It is hoped that a better understanding of migraine will
eventually pave the way for effective targeted treatment options.
Conclusions
Increased GABA levels were associated with increased pain and more frequent
central sensitization symptoms in migraine. These findings contribute to the understanding
of migraine. These findings also provide early evidence for the usefulness of measuring
GABA and pain and central sensitization in characterizing migraine better and broadening the
diagnostic process. In addition to enhancing diagnosis and assessment, using self-report
questionnaires in clinical practice may facilitate understanding of a patient’s headache
142
experience. This new information on the association of clinical characteristics of GABA
levels in migraine brings us a step closer to demonstrating the validity of GABA as a
migraine biomarker.
Acknowledgements
We thank all the participants for willingly volunteering their time and the staff of the
Southern Radiology Group at The University of Sydney Brain and Mind Centre for their
support during the conduct of this study.
143
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Figure Legends
Figure 1. Placement of the single voxel in the (A) axial, (B) coronal, and (C) sagittal planes
for proton magnetic resonance spectroscopy analysis
Figure 2. Typical locations of headache as reported by participants with migraine (visual
representation according to percentage of participants reporting the site of pain)
Figure 3. Top and bottom five pain descriptors chosen by participants with migraine to
describe their headaches (n = 20)
Figure 4. Scatterplot with regression line showing positive association between brain GABA
levels and scores on (A) Short-form McGill Pain Questionnaire-2 (ρ = .47, P =
0.04) and (B) Central Sensitization Inventory (ρ = .48, P = 0.03) in the migraine
group (n = 20)
Figure 5. Receiver operating characteristic curve evaluating CSI scores of people with
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152
Table Legends
Table 1. Descriptive migraine characteristics (n = 20)
Table 2. Association of GABA levels and clinical characteristics of migraine using
Spearman’s rho, ρ, or Kendall’s tau, τ, correlation coefficient (P values)
Table 3. Comparison of clinical characteristics based on self-report questionnaires between
migraine and control groups (n = 40)
153
Figure 1. Placement of the single voxel in the (A) axial, (B) coronal, and (C) sagittal planes
for proton magnetic resonance spectroscopy analysis
154
Figure 2.Typical locations of headache as reported by participants with migraine (visual
representation according to percentage of participants reporting the site of pain)
155
Figure 3.Top and bottom five pain descriptors chosen by participants with migraine to
describe their headaches (n = 20)
156
Figure 4. Scatterplot with regression line showing positive association between brain GABA
levels and scores on (A) Short-form McGill Pain Questionnaire-2 (ρ = .47, P =
0.04) and (B) Central Sensitization Inventory (ρ = .48, P = 0.03) in the migraine
group (n = 20)
157
Figure 5.Receiver operating characteristic curve evaluating CSI scores of people with
migraine and controls. Area under the curve = 0.88 (95% confidence interval
0.76-1.00), P<0.001
158
Table 1. Descriptive migraine characteristics (n = 20)
MEAN (SD) MEDIAN (IQR) n %
Migraine history (years since first episode) 17.6 (14.6) 15 (5.0-24.0)
Frequency of headache in a month (n) 5.1 (5.2) 2.8 (1.5-8.5)
Episode duration (hours) 38.6 (21.8) 48.0 (24.0-48.0)
Average headache intensity last month (0-10) 6.4 (1.8) 6.0 (6.0-8.0)
Unilateral 13 65
With aura 9 45
Nausea 18 90
Vomiting 6 30
Photophobia / Phonophobia
Both photophobia and phonophobia 13 65
Photophobia alone 6 30
Phonophobia alone 0 0
Neither photophobia nor phonophobia 1 5
Physical activity intolerance 15 75
159
Table 2. Association of GABA levels and clinical characteristics of migraine using
Spearman’s rho, ρ, or Kendall’s tau, τ, correlation coefficient (P values)
GABA LEVELS
Correlation Coefficients (P values) 1
Headache characteristics
Migraine history ρ = -.40 (0.08)
Frequency of headache in a month τ = .16 (0.33)
Episode duration τ = -.01 (0.94)
Average headache intensity last month ρ = .17 (0.48)
Pain and sensitization
SF-MPQ-2 Total score ρ = .47 (0.04)2
SF-MPQ-2 Continuous pain score ρ = .21 (0.38)
SF-MPQ-2 Intermittent pain score τ = .33 (0.04)b
SF-MPQ-2 Neuropathic pain score τ = .37 (0.03)b
SF-MPQ-2 Affective descriptors ρ = .49 (0.03)b
CSI Total score ρ = .48 (0.03)b
Emotional state
DASS-21 Depression Score τ = -.14 (0.42)
DASS-21 Anxiety Score τ = .17 (0.34)
DASS-21 Stress Score τ = -.13 (0.43)
Disability (HIT-6 score) ρ = .06 (0.79)
1
Spearman's rho, ρ; Kendall’s tau, τ
2
Correlation is significant at the 0.05 level (2-tailed)
160
Table 3. Comparison of clinical characteristics based on self-report questionnaires between migraine and control groups (n = 40)
MIGRAINE (n =20) CONTROL (n = 20) Glass’s  P values

Mean (SD) Median (IQR) Mean (SD) Median (IQR)
SF-MPQ-2 Total score 2.2 (1.5) 2.3 (0.8-3.1) 0.0 (0.1) 0.0 (0-0) 1.47 <0.001
SF-MPQ-2 Continuous pain 3.3 (1.6) 3.7 (2.0-4.4) 0.1 (0.2) 0.0 (0-0) 2.00 <0.001
score
SF-MPQ-2 Intermittent pain 2.3 (2.3) 1.7 (0.7-3.2) 0.0 (0.0) 0.0 (0-0) 1.00 <0.001
score
SF-MPQ-2 Neuropathic .9 (1.2) 0.3 (00-1.2) 0.0 (0.2) 0.0 (0-0) 0.75 0.006
pain score
SF-MPQ-2 Affective 2.5 (2.0) 2.2 (1.0-3.8) 0.1 (0.2) 0.0 (0-0) 1.2 <0.001
descriptors
CSI Total score 35.0 (9.6) 32.0 (30-42.5) 16.2 (11.8) 14.0 (9.0-20.5) 1.96 <0.001
Emotional state
DASS-21 Depression score 3.4 (3.9) 2.0 (0-6.0) 0.8 (1.1) 0.0 (0-1.0) 0.67 0.005
DASS-21 Anxiety score 3.1 (3.6) 2.0 (0-5.0) 1.5 (2.4) 0.0 (0-3.0) 0.44 0.095
DASS-21 Stress score 9.2 (8.2) 8.0 (2.0-11.0) 3.2 (3.6) 2.0 (0-6.0) 0.73 0.006
Disability
HIT-6 Total score 1 61.6 (7.6) 63.0 (57.2-65.5) 38.5 (5.1) 36.0 (36-39.5) 3.05 <0.001
1
HIT-6 scores range from 36 to 78; score less than 49 = little or no impact (grade 1), score 50–55 = moderate impact (grade 2), score 56–59 = substantial impact
(grade 3), and score equal to or greater than 60 = severe impact (grade 4).
161
Highlights
• Increased GABA levels were associated with increased pain and more frequent
central sensitization symptoms in migraine.
• Results provide preliminary evidence for the possible involvement of GABA in
migraine pathophysiology.
• GABA is a potential biomarker for migraine.
• Measuring clinical characteristics of migraine using self-report questionnaires may be
useful in characterizing migraine better and broadening the diagnostic process.
162
CHAPTER FIVE
Characterizing Cervical Musculoskeletal Impairments and
Patient Experience in Migraine as Distinguished from
Non-Migraine Headaches
Chapter Five has been submitted as:
Aguila ME, Leaver AM, Hau SA, Ali K, Ng K, Rebbeck T. Characterizing cervical
musculoskeletal impairments and patient experience in migraine as distinguished from non-
migraine headaches. Submitted to The Journal of Headache and Pain.
163
As co-authors ofthe paper “Characterizing cervical musculoskeletal impairments and patient
experience in migraine as distinguished from non-migraine headaches”, we confirm that
Maria Eliza Ruiz Aguila has madethe following contributions:
Signed: Stephanie Amelia Hau Date: 31 March 2017
Signed: Kanzah Ali Date: 31 March 2017
Signed: Karl Ng Date: 31 March 2017
164
Manuscript title: Characterizing cervical musculoskeletal impairments and patient
experience in migraine as distinguished from non-migraine headaches
Authors: Maria-Eliza R. Aguila, MPhysio1,2,Andrew M. Leaver, PhD1, Stephanie Amelia
Hau, BAppSci (Phty) (Honours)1, Kanzah Ali, BAppSci (Phty) (Honours)1, Karl Ng, PhD3,
Trudy Rebbeck, PhD1,4
Authors’institutional information:
1
2
3
Department of Neurology, Royal North Shore Hospital, University of Sydney
4
Authors’ e-mail addresses:
[email protected]
165
Andrew M. Leaver
[email protected]
Stephanie Amelia Hau
[email protected]
Kanzah Ali
[email protected]
Karl Ng
[email protected]
Trudy Rebbeck
[email protected]
Corresponding author:
Maria-Eliza R Aguila
[email protected]
Telephone number: (+632) 5267125
Fax number: (+632) 5262271
166
1 Abstract
2 Background:Symptoms of migraine may vary and overlap with those of other recurrent
3 headache types, including tension-type headache and cervicogenic headache. Thus diagnosis
4 and treatment of migraine may potentially be challenging. Cervical musculoskeletal
5 impairments may help characterize migraine further but available evidence is inconsistent.
6 Patient experience of disability and multidimensional pain is also important to detail to
7 possibly differentiate migraine from other recurrent headaches.This research aimed to
8 distinguishmigraine from non-migraine headaches(tension-type headache and cervicogenic
9 headache) based on cervical musculoskeletal impairment and patient experience.
10 Methods:In this cross-sectional study, participants with migraine and non-migraine
11 headaches and headache-free controlsunderwent physical examination for cervical
12 musculoskeletal impairment and completed questionnaires on patient experience (disability,
13 multidimensional pain, central sensitization, and emotional state).
14 Results:Fewer participants in the migraine group [n (%) 4 (10%)] had cervical articular
15 impairment than the non-migraine group [26 (58%); p < 0.001]. Headache groups did not
16 differ on cervical muscle impairment measures when considered independently. Migraine
17 group had more intense pain [median numeric rating scale/10 (IQR)] 7.0 (6.0–7.0) versus 5.0
18 (4.0–7.0); p = 0.009] and higher disability scores [e.g. Headache Disability Questionnaire
19 43/90 (31–53) versus 27/90 (20–42); p = 0.006] than the non-migraine group. A combination
20 of no pain on manual examination of the cervical spine, less change in deep cervical
21 extensors thickness during contraction, less frequent headaches, and higher disability scores
22 had 80.0% sensitivity and 75.6% specificity in identifying migraine.
23 Conclusions: Less cervical musculoskeletal impairment and higher pain and self-reported
24 disability, considered independently, distinguished migraine from non-migraine headaches.
25 New evidence is presented on cervical muscle behavior measured using the deep cervical
167
26 extensor test and self-reported disability as part of a combination of clinical characteristics
27 that distinguishes migraine. Thus results suggest the value of assessing impairments and
28 disability in migraine for differential diagnosis.
29
30 Key words: migraine, tension-type headache, cervicogenic headache, disability, cervical
31 spine, musculoskeletal impairment
32
168
33 Background
34 The most common recurrent headaches that present to primary care clinicians and specialists,
35 namely migraine, tension-type headache (TTH) [1] and cervicogenic headache (CGH) [2], are
36 among the most disabling headache types. One critical element in reducing the burden of
37 headaches is effective targeted headache treatment. Effective headache treatment, in turn,
38 requires a clear understanding of underlying disease mechanisms, well-defined distinction of
39 clinical features between headache types, and ultimately, accurate diagnosis.
40 Distinguishing migraine from other headache types is relevant because migraine is the
41 most disabling headache globally [3], yet is underdiagnosed [4]. Contributing to this
42 difficulty in diagnosis are the complex and varied presentations of migraine within and
43 between individuals and its possible coexistence with other headache types [4, 5]. Migraine
44 features may also overlap with those of other headaches, plausibly due to the common
45 involvement of the trigeminocervical complex in the brainstem in different headache types,
46 including TTH and CGH [6, 7].The bidirectional interaction between nociceptive input from
47 the upper cervical spine and the trigeminocervical complex [8, 9] are hypothesized to result
48 in cervical symptoms that are commonly associated with recurrent headaches [10,
49 11]. Consequently, cervical musculoskeletal impairment has been treated in headaches,
50 although with variable evidence on effects [9]. To date, it is unknown whether these
51 characteristics distinguish migraine from other frequently presenting recurrent headache
52 types.
53 Therefore a conceivable way to better distinguish migraine, in addition to those listed
54 as diagnostic criteria in International Classification of Headache Disorders (ICHD) [5], is by
55 assessing symptoms and musculoskeletal impairments arising from the cervical spine [10,
56 12]. It is plausible that migraine differs from non-migraine headaches in terms of cervical
57 impairments. Migraine primarily involves central nociceptive processing while episodic non-
169
58 migraine headaches, specifically TTH and CGH, are hypothesized to be primarily initiated by
59 peripheral nociceptive mechanisms [5, 7, 13]. By clarifying whether or not cervical
60 musculoskeletal impairment distinguished migraine, we improve the understanding of
61 migraine especially when its presentation is complex. This improved understanding, then,
62 would help address the issue of underdiagnosis of migraine.
63 To build on knowledge from previous studies and clarify the distinction of migraine
64 from other frequently presenting recurrent headaches, a comprehensive examination of
65 cervical musculoskeletal impairment is warranted. A recent Delphi study that assembled a
66 panel of expert physiotherapists recommended the use of tests for cervical musculoskeletal
67 impairment in headache assessment, including tests previously reported as discriminatory for
68 CGH [14]. Moreover, impairment of the cervical extensor muscle group in headache was
69 proposed to require further investigation [15]. Additionally, cervical musculoskeletal
70 impairment in headaches will be better understood when differentiated from those in
71 headache-free controls, considering the high prevalence of neck pain in the general
72 population [3].
73 In addition to understanding cervical musculoskeletal impairment in headaches more
74 thoroughly, understanding symptoms from a multidimensional biopsychosocial perspective
75 may potentially assist in distinguishing migraine from other headaches. Currently, the ICHD
76 lists unidimensional characteristics of pain, such as quality and severity, among the criteria
77 for classifying headaches [5]. However, these pain characteristics may overlap between
78 headache types. For example, 35.1% of individuals with TTH reported moderate to severe
79 headaches [16], which are severity ratings typically associated with migraine [5]. Therefore,
80 a multidimensional assessment of pain, complemented by information about disability and
81 other characteristics that modulate the pain experience, such as central sensitization
170
82 mechanisms [17] and emotional states [18], may provide the opportunity to understand the
83 patient experinece better and distinguish migraine from other headache types.
84 This study therefore aimed to determine if migraine can be distinguished from
85 frequently presenting non-migraine headaches (TTH and CGH) based on a comprehensive
86 assessment of cervical musculoskeletal impairment and patient experience. Clarifying the
87 distinction between migraine and non-migraine headaches would contribute to a better
88 understanding of frequently presenting headaches, an enhanced diagnostic framework, and
89 eventually research directions for better, targeted treatments for these headache types.
90
91 Methods
92 Design
93 In this cross-sectional study, we compared characteristics between people with migraine,
94 those with non-migraine headaches and headache-free controls. This research was granted
95 ethics approval by the Human Research Ethics Committee of The University of Sydney
96 (Project Number 2014/536).
97
98 Participants
99 We recruited volunteers aged 18 to 65 with recurrent headache and headache-free controls
100 through advertisements posted at community bulletins, social media, and primary and
101 specialist care clinics. Participants in the headache group were included if they had headaches
102 for at least one year and had at least one headache episode in the previous month. Headache
103 participants were further classified into the migraine group (fulfilling the criteria for
104 migraine only and not those for other headache types) or non-migraine group (with primary
105 diagnosis of TTH and/or CGH, with or without comorbid migraine) using the ICHD-3 beta
171
106 criteria [5]. Participants in the control group were included if they had not experienced any
107 headache in the past 3 months.
108 Exclusion criteria for the headache groups were other known secondary headache
109 classifications without a known pathogenesis in the neck, such as tumor, substance
110 withdrawal, etc., and psychiatric disorders. Exclusion criteria for the control group were
111 severe neck pain, recent head or neck surgery, or conditions requiring medical attention or
112 affecting performance of daily activities.
113
114 Procedure
115 All participants underwent initial telephone screening to confirm their eligibility. All eligible
116 participants provided written informed consent prior to participation.Eligible participants then
117 completed questionnaires that provided information about demographic and headache
118 characteristics as well as their disability and multidimensional pain experience. Participants
119 also attended one assessment session for interview about headache features and physical
120 examination of cervical musculoskeletal impairment. Physical examination was done by a
121 physiotherapist with 20 years of experience for the headache groups and by two novice
122 physiotherapists for the control group. All examiners were trained by a specialist
123 musculoskeletal physiotherapist with clinical and research expertise in cervical spine
124 disorders. Participants were independently classified into migraine and non-migraine
125 groups by two researchers using the ICHD-3 beta criteria. Disagreements were resolved by a
126 third researcher. The process was overseen by a neurologist and a specialist physiotherapist
127 who were blinded to the headache diagnoses of participants and who did not conduct the
128 physical examination.
129
130 Outcomes
172
131 Cervical musculoskeletal impairment comprised cervical articular impairment and cervical
132 muscle impairment. Cervical articular impairment was measured using the range of motion
133 measures, flexion rotation test [19] and manual examination of the upper cervical spine with
134 passive accessory intervertebral movements (PAIVMs) [12, 20]. The Cervical Range of
135 Motion Instrument (CROM) 3 (Performance Attainment Associates, (Roseville, MN, USA)
136 was used to measure flexion, extension, lateral flexion and rotation, summed to obtain the
137 composite score. The flexion rotation test was deemed positive if headache was provoked and
138 the range of movement was ≤ 32o [21]. Manual examination of the cervical spine was deemed
139 positive if headache was provoked.
140 Cervical muscle impairment was assessed in terms of muscle function (relating to
141 strength and endurance) and muscle behavior (relating to motor control). Cervical flexor and
142 extensor strength was measured using the Lafayette Manual Muscle Tester (Model 01163)
143 handheld dynamometer [22]. Cervical extensor and flexor endurance was measured using the
144 protocol published by Edmondston and colleagues [23]. Upper limits for sustained isometric
145 contraction were set at 60 seconds for flexors and 200 second for extensors [23]. Ratios of
146 extensor to flexor strength and endurance were calculated.
147 Muscle behavior of the deep flexor and deep extensor muscles were assessed using
148 the cranio-cervical flexion test [24], cervical extensor test [25], and the deep cervical extensor
149 (DCE) test. The DCE test measures changes in thickness of the deep cervical
150 extensor muscle group during low-load using ultrasound imaging [26]. Performance on the
151 cranio-cervical flexion test was scored using the performance index, which was calculated
152 based on the number of times the participant could hold the pressure level achieved for 10
153 seconds [24]. The cervical extensor test was scored through video analysis of the
154 performance of the participant. The performance of correct movement patterns in maintaining
155 the start position and during the eccentric and concentric phases of movement were scored on
173
156 a scale of 0–4, with lower scores indicating better performance. The aggregate score, which is
157 the total of scores for all phases, was reported.
158 In contrast to the cervical extensor test, the DCE test measures changes in thickness of
159 the deep cervical extensor muscle group during low-load contractions using ultrasound
160 imaging [26]. Thickness of the deep cervical extensors was measured from real-time
161 ultrasound images from the top edge of the lamina to the leading edge of the first fascial
162 plane above the facet joint or spinous process at C4 level [26]. Measurements were done with
163 the muscles at rest and during submaximal contraction. Measurements were taken from the
164 symptomatic side for participants with side-locked headaches. For participants whose
165 headaches were bilateral and for control participants, measurements from the left and right
166 muscle groups were averaged and recorded as the measure for both sides. Analyses of the
167 DCE test were based on the change in thickness of the muscles from the relaxed state to the
168 contracted state and the percentage change in thickness (that is, the difference between
169 contracted and relaxed state divided by the relaxed state multiplied by 100%).
170 Aspects of patient experience assessed in this studycomprised disability,
171 multidimensional pain, central sensitization, and emotional state using the Henry Ford
172 Headache Disability Inventory (HDI) [27], Headache Disability Questionnaire (HDQ)
173 [28],Headache Impact Test-6TM (HIT-6) [29], World Health Organization Disability
174 Assessment Schedule 2.0 (WHODAS) [30], Short-form McGill Pain Questionnaire-2 (SF-
175 MPQ-2) [31], Central Sensitization Inventory (CSI) [32], and Depression Anxiety Stress
176 Scales-21 (DASS-21) [33].
177
178 Statistical analysis
179 The calculated sample size (n = 32 per group) was based on a hypothesized mean difference
180 of 20 degrees in range of cervical extension and 20 Newtons in strength between migraine
174
181 and non-migraine groups [10] and an estimated within-group standard deviation of 35
182 units,with a significance level of 0.05 with 80% power. Allowing for about 20% attrition, we
183 determined the sample size to be 40 per group.
184 Distributions of data were examined through visual inspection and using the Shapiro-
185 Wilk test and summarized using descriptive statistics. Comparisons of the continuous
186 variables between migraine, non-migraine and control groups were computed using one-way
187 ANOVA followed by Fisher’s least significant difference (LSD) post-hoc test when there was
188 an overall significance. Kruskal-Wallis test was used when the assumption of homogeneity of
189 variance was not met (Levene’s test, p< 0.05), followed by pairwise-comparisons using
190 Mann-Whitney Test with Bonferroni correction. Additionally, comparisons for headache
191 characteristics and pain and disability questionnaire scores between the migraine and non-
192 migraine groups only were computed using the T-test or Mann-Whitney Test, as appropriate.
193 Comparisons of categorical variables between the three groups were computed using the Chi
194 square test, followed by post-hoc test with modified Bonferroni correction when there was an
195 overall significance.For characteristics that were significantly different between headache
196 groups, area under the receiver operating characteristic (ROC) curve analysis was used. The
197 discriminative ability of these characteristics were examined by computing for optimal cutoff
198 value, area under the curve (AUC), sensitivity, specificity, and positive likelihood ratio.
199 Stepwise discriminant analysis was used to identify the combination of characteristics that
200 distinguished migraine from non-migraine headaches. The criteria for entry and removal of
201 variables into the model were a significance level of p< 0.05 and p< 0.10, respectively, of
202 Wilks lambda.Statistical analyses were conducted using Statistical Package for Social
203 Sciences® statistical software, version 24 (SPSS Inc., Chicago, Illinois, USA) for Windows.
204 Significance level was set at 0.05.
205
175
206 Results
207 Participants
208 Forty people with migraine, 45 people with non-migraine headache, and 40 controls
209 participated in this study. The non-migraine group comprised 26 participants with
210 predominantly CGH, 16 participants with predominantly TTH, and three participants with
211 both cervicogenic and TTHs. The flow of participants through the study and reasons for
212 exclusion of volunteers are shown in Figure 1.The demographic and headache characteristics
213 of the participants are presented in Table 1 and Table 2, respectively. There were significant
214 differences between the migraine and non-migraine groups in headache characteristics. The
215 migraine group had longer history of headache [median (interquartile range, IQR) 18.50
216 (10.50–24.50) years versus 9.00 (4.00–20.00) years; p = 0.002], higher average headache
217 intensity in the last month [7.00 (6.00–7.00) versus 5.00 (4.00–7.00); p = 0.009], and less
218 frequent headaches in a month [3.00 (1.00–5.00) versus 8 (3.50–13.00); p < 0.001] than the
219 non-migraine group. More participants in the migraine group compared to the non-migraine
220 group had unilateral headache [n (%) 32 (80.00%) versus 20 (44.44%); p = 0.001] and
221 experienced vomiting [20 (50.00%) versus 13 (28.89%); p = 0.046], and photophobia and/or
222 phonophobia [36 (90.00%) versus 26 (57.78%), p = 0.001] with their headaches.
223
224 Cervical musculoskeletal impairment
225 There were significant differences between groups in cervical range of extension, pain on
226 flexion rotation test, manual examination of the upper cervical joints, and ratio of extensor-
227 flexor strength (Table 3). Post-hoc analyses revealed that the migraine differed from the non-
228 migraine group but not from the control group on cervical articular impairments. Specifically,
229 fewer participants in the migraine [4 (10.00%)] and control groups [6 (15%)] tested positive
230 on the flexion rotation test compared to participants in the non-migraine group [17
176
231 (37.78%)] (p = 0.003–0.018). Similarly, fewer participants in the migraine group [4 (10.00%)]
232 and control group [0 (0%)] had their headaches provoked on manual examination of the
233 upper cervical joints compared to participants in the non-migraine group [n (%) 26 (57.78%)]
234 (p< 0.001). The migraine group had lower ratio of extensor-flexor strength than the control
235 group [1.51 (1.16–1.85) versus 2.15 (1.66–2.64);(p< 0.001)]. The migraine group did not
236 differ from the non-migraine group on all cervical muscle impairment measures (p> 0.05).
177
237 Table 1. Demographic characteristics of participants (n = 125)*
Median (IQR) or n (%) p

values †
Migraine Non-Migraine Control
(n = 40) (n = 45) (n = 40)
Age 42.00 (28.50–49.50) 29.00 (27.00–42.00) 31.50 (22.00–50.50) 0.06

Gender (female) 32 (80.00%) 40 (88.89%) 31 (77.50%) 0.35
Body mass index 23.44 (21.18–27.62) 22.48 (20.64–27.06) 23.12 (21.26–24.79) 0.69
Marital status 0.48
Single / Divorced / 20 (50.00%) 28 (62.22%) 21 (52.50%)
Widowed / Separated
Married / De facto 20 (50.00%) 17 (37.78%) 19 (47.50%)
Region of birth 0.048
Oceania 27 (67.50%) 24 (53.33%) 16 (40.00%)
Other geographic region 13 (32.50%) 21 (46.67%) 24 (60.00%)
Level of education 0.08

University degree 33 (82.50%) 40 (88.89%) 29 (72.50%)
No university degree 6 (15.00%) 4 (8.89%) 11 (27.50%)
No information provided 1 (2.50%) 1 (2.22%)
Occupation 0.001
Professional 13 (32.50%) 26 (57.78%) 13 (32.50%)
Student 9 (22.50%) 12 (26.67%) 20 (50.00%)
Other occupation 18 (45.00%) 7 (15.56%) 7 (17.50%)
238
Abbreviation: IQR, interquartile range

NOTE. Bold numbers indicate statistical significance (p< 0.05) or statistically significant difference from the other groups on
post-hoc analyses
*
For continuous variables, values are presented as median (IQR); for categorical variable, valuesare presented as frequency (%)
†
pvalues for Kruskal-Wallis Testfor continuous variables between three groups; p values for Chi-square test for categorical
variables between three groups
178
239 Table 2. Headache characteristics of participants with recurrent headaches (n = 85)‡
Median (IQR) orn (%) p values §
Migraine Non-Migraine
(n = 40) (n = 45)
History of headache (years since first 18.50 (10.50–24.50) 9.00 (4.00–20.00) 0.002
episode)
Frequency of headache in a month 3.00 (1.00–5.00) 8 (3.50–13.00) <0.001
Episode duration , minimum (hours) 3.50 (1.50–24.00) 4 (2.00–24.00) 0.96
Episode duration , maximum (hours) 60.00 (30.00–72.00) 24.00 (12.00–72.00) 0.11
Average headache intensity last month 7.00 (6.00–7.00) 5.00 (4.00–7.00) 0.009
(0-10)**
Unilateral location 32 (80.00%) 20 (44.44%) 0.001
Throbbing / pulsating quality 31 (77.50%) 27 (60.00%) 0.08
Associated with nausea 35 (87.50%) 32 (71.11%) 0.07
Associated with vomiting 20 (50.00%) 13 (28.89%) 0.046
Associated with 36 (90.00%) 26 (57.78%) 0.001
photophobia/phonophobia
Associated with physical activity 17 (42.50%) 18 (40.00%) 0.82
intolerance
Pharmacologic treatment (number of
participants, n, %)
Paracetamol 14 (35.00%) 17 (37.78%) 0.06
Non-steroidal anti-inflammatory 18 (45.00%) 20 (44.44%) 0.58
drug
Tricyclic antidepressant 6 (15.00%) 3 (6.67%) 0.47
Triptan 19 (47.50%) 10 (22.22%) 0.006
Botulinum toxin 8 (20.00%) 11 (24.44%) 0.48
Beta blocker 4 (10.00%) 3 (6.67%) 0.42
Selective serotonin reuptake 5 (12.50%) 6 (13.33%) 0.64
inhibitor
Proton pump inhibitor 4 (10.00%) 6 (13.33%) 0.42
Anticonvulsant 5 (12.50%) 7 (15.56%) 0.29
Contraceptive 7 (17.50%) 10 (22.22%) 0.99
240

NOTE. Bold numbers indicate statistical significance (p<0.05)
‡
For continuous variables, values are presented median (IQR); for categorical variables, valuesare presented as
frequency (%)
§
pvalues for Mann-Whitney Testfor continuous variables between groups; p values for Chi-square test for
categorical variables between groups
**
Headache intensity: Numerical rating scale 0–10; 0= no pain, 10 = worst possible pain
179
241 Table 3. Comparison of performance on cervical musculoskeletal impairment tests between participant groups (n = 125)††
Median (IQR) or n (%) p values ‡‡

(n = 40) (n = 45) (n = 40)
Cervical range of motion
Extension 70.00 (60.00–70.00) 60.00 (60.00–70.00) 75.00 (62.50–80.00) 0.037
Composite score 355.00 (312.50–372.50) 349.00 (315.00–375.00) 368.00 (327.50–421.50) 0.14
Upper cervical joint dysfunction (n, %)
Positive flexion rotation test 4 (10.00%) 17 (37.78%) 6 (15.00%) 0.004
Pain on manual examination of the upper 4 (10.00%) 26 (57.78%) 0 (0.00%) <0.001
cervical joints
Muscle performance
Ratio of extensor-flexor strength 1.51 (1.16–1.85) 1.36 (1.20–1.64) 2.15 (1.66–2.64) <0.001
Ratio of extensor-flexor endurance 3.33 (3.24–5.41) 3.33 (2.25–3.33) 3.33 (2.44–4.26) 0.34
Neuromotor control
Cranio-cervical flexion test 18.00 (6.00–30.00) 8.00 (6.00–26.00) 17.00 (12.00–30.00) 0.09
performance index
Cervical extensor test aggregate 3.00 (3.00–4.50) 3.00 (3.00–5.00) 3.00 (3.00–5.00) 0.99
score
Deep cervical extensor test§§
Percent change on symptomatic 5.13 (1.72–10.18) 7.47 (3.07–16.30) 8.44 (3.40–14.60) 0.19
side
Percent change on asymptomatic 7.34 (3.19–10.85) 9.32 (6.35–16.30) 8.44 (3.40–14.60) 0.11
side

NOTE. Bold numbers indicate statistical significance (p<0.05) or statistically significant difference from the other groups on post-hoc analyses
††
For continuous variables, values are presented as median (IQR); for categorical variables are presented as frequency (%)
‡‡
p values for Kruskal-Wallis Testfor continuous variables between three groups; p values for Chi-square test for categorical variables between three groups
§§
Difference in thickness between relaxed and contracted deep cervical extensor muscle
242 Measurement of patient experience using self-report questionnaires
243 There were significant differences between groups on all questionnaire scores (Table 4).
244 Post-hoc analyses revealed that the migraine group had significantly higher scores than the
245 non-migraine group on HDI Total Score [median (IQR) 40 out of 100 (21–56) versus 24 out
246 of 100 (14–44), p = 0.029] and HDQ score [43 out of 90 (31–53) versus 27 (20–42), p =
247 0.006]. For all other questionnaires, the control group had significantly lower scores than the
248 headache groups;however there was no difference between headache groups.
249 Total scores on HDI appeared to have good diagnostic value in classifying individuals
250 as having migraine and not non-migraine headache (AUC = 0.80; 95% confidence interval,
251 CI, 0.73 to 0.88; p< 0.001). The optimal HDI cutoff score to distinguish people with migraine
252 from non-migraine headaches was 19 out of 100, with sensitivity of 80.0% and specificity of
253 67.1%, and positive likelihood ratio of 1.72. Similarly, HDQ score appeared to have good
254 diagnostic value in classifying individuals as having migraine or not (AUC = 0.82; 95% CI
255 0.75 to 0.90; p<0.001). The optimal HDQ cutoff score to distinguish people with migraine
256 from non-migraine headaches was 27.5 out of 90, with sensitivity of 80.0%, specificity of
257 74.1%, and positive likelihood ratio of 3.09.
181
258 Table 4. Comparison of scores on self-report questionnaires between participant groups (n = 125)

(n = 40) (n = 45) (n = 40)
Mean (SD) Median (IQR) Mean (SD) Median (IQR) Mean (SD) Median (IQR) p
values ***
Disability
HDI Total Score ††† 39.45 (23.01) 40.00 (21.00–56.00) 30.49 (21.78) 24.00 (14.00–44.00) 0.029
HDQ ‡‡‡ 41.60 (15.68) 43.00 (31.00–53.00) 31.67 (16.04) 27.00 (20.00–42.00) 0.006
HIT-6 Total score §§§ 62.10 (5.60) 62.00 (58.00–65.50) 58.67 (6.34) 60.00 (54.00–63.00) 0.06
WHODAS 2.0 Overall 13.65 (13.20) 10.42 (4.17–19.79) 11.62 (10.39) 6.25 (4.17–20.83) 1.09 (3.56) 0.00 (0.00–0.00) 0.70
score‡‡‡
Pain
SF-MPQ-2 Total score **** 2.25 (1.71) 1.98 (0.95–2.66) 1.96 (1.39) 1.64 (1.00–2.59) 0.08 (0.20) 0.00 (0.00–0.02) 0.55
Central sensitization
CSI Total score †††† 35.78(14.03) 34.50 (26.50–45.50) 37.16 (12.03) 37.00 (31.00–42.00) 18.80 (8.86) 18.50 (12.00–25.50) <0.001
Emotional state ‡‡‡‡

DASS-21 Depression score 2.55 (3.64) 1.00 (0.00–3.50) 2.16 (2.32) 1.00 (0.00–4.00) 0.85 (1.61) 0.00 (0.00–1.00) 0.002
DASS-21 Anxiety score 2.18 (3.39) 1.00 (1.00–3.00) 2.04 (2.34) 1.00 (0.00–3.00) 0.93 (1.42) 0.00 (0.00–1.50) 0.004
DASS-21 Stress score 5.35 (4.07) 4.50 (2.50–8.00) 4.91 (3.79) 4.00 (2.00–6.00) 2.55 (2.88) 1.50 (0.00–4.50) 0.001
259
Abbreviations: CSI, Central Sensitization Inventory; DASS, Depression Anxiety Stress Scales-21; HDI, The Henry Ford Headache Disability Index; HDQ, Headache Disability Questionnaire; HIT-6, Headache
Impact Test-6; IQR, interquartile range; SD, standard deviation; SF-MPQ-2, Short-form McGill Pain Questionnaire-2; WHODAS, World Health Organization Disability Assessment Schedule
NOTE. Bold numbers indicate statistical significance (p<0.05) or statisticallysignificant difference from the other groups on post-hoc analyses
***
pvalues for ANOVA for CSI scores; pvalues for Mann-Whitney Test for SF-MPQ-2, HDI, HDQ and HIT-6 scores; pvalues for Kruskal-Wallis Testfor WHODAS and DASS scores
†††HDI Total Scores and WHODAS Overall Scores range from 0 to 100, with higher scores reflecting greater disability caused by the headache
‡‡‡
HDQ scores range from 0 to 90, with higher scores reflecting greater disability caused by the headache
§§§
HIT-6 scores range from 36 to 78; a score <49 indicates little or no impact (grade 1); a score of 50 to 55 indicates moderate impact (grade 2); a score of 56 to 59 indicatessubstantial impact (grade 3), and
score>60 indicates severe impact (grade 4).
****
SF-MPQ-2 Total Scores range from 0 (no pain) to 10 (worst pain possible)
††††
CSI scores range from 0 to 100, with higher scores reflecting a higher degree of sensitization
‡‡‡‡
DASS scores range from 0 (normal) to 21 (extremely severe)
260 Combination of characteristics predictive of migraine
261 Discriminant analysis of characteristics revealed significant differences between the migraine
262 and non-migraine groups (Wilk’s lambda = 0.60, Chi square =49.22, p< 0.001). The
263 discriminant function for characteristics explained 100% of the variance in the groups (p<
264 0.001). A combination of no pain on manual examination of the cervical spine, less change
265 on the DCE test, less frequent headaches, and higher disability scores predicted migraine
266 (Table 5). This prediction model for migraine correctly classified 80.0% of the original
267 grouped cases with a sensitivity of 80.0% and specificity of 75.6% for migraine (Table 6).
268
269
270 Table 5. Discriminant function coefficients (standardized coefficients) for characteristics with
271 highest predictive ability for migraine
Characteristics Discriminant Function

Coefficient
Pain on manual examination of the upper cervical 0.736

joints
Frequency of headache 0.523
Headache Impact Test Total Score -0.513
Percent change in thickness of deep cervical extensor 0.468

muscle from relaxed state on symptomatic side
272
183
273 Table 6. The sensitivity and specificity of characteristics to categorize migraine from participants with non-migraine headaches (n = 85)
274
Predicted Group Membership
Non-Migraine and
Group Migraine Mixed Headaches Total
Original Count Migraine 33 7 40

classification Non-Migraine and Mixed 10 35 45
Headaches
Sensitivity / Migraine 82.5% 17.5% 100.0%

Specificity Non-Migraine and Mixed 22.2% 77.8% 100.0%
Headaches
Cross-validated Count Migraine 32 8 40

Non-Migraine and Mixed 11 34 45
Headaches
Sensitivity / Migraine 80.0% 20.0% 100.0%

Specificity Non-Migraine and Mixed 24.4% 75.6% 100.0%
Headaches
275
184
276 Discussion
277 Our results provide information on characteristics that distinguished migraine from non-
278 migraine headaches. Our results indicate that cervical articular impairmentwas worse in
279 people with non-migraine headaches than in people with migraine, while cervical muscle
280 impairmentwas not different between headache groups. In contrast, headache intensity and
281 self-reported disability were worse in migraine than non-migraine headaches. A combination
282 of information on cervical musculoskeletal impairment, headache characteristic and self-
283 reported disability distinguished migraine from non-migraine headaches. These
284 characteristics that distinguished migraine from non-migraine headaches may be assessed to
285 enhance diagnosis especially for complex presentations of migraine.
286 Cervical articular impairment was significantly less in the migraine group than the
287 non-migraine group in our study, as would be expected. Specifically, both the flexion rotation
288 test [19] and headache provocation with upper cervical spine manual examination [12,
289 20] more frequently had positive findings in participants with non-migraine headaches than
290 those with migraine. Our results therefore corroborate previousstudies that demonstrated
291 impairments on these tests in people with non-migraine headache, specifically CGH,but not
292 in people with migraine and controls [10,12, 34]. Interestingly, more than half of the
293 participants in both headache groups in the present study reported neck pain.The coexistence
294 of neck pain in headaches is consistent with the hypothesized bidirectional interaction
295 between nociceptive input from upper cervical spine and the trigeminocervical complex [8].
296 Our findings therefore support examining the upper cervical joints to differentiate migraine
297 from non-migraine headache when neck pain coexists. Doing so would augment the ICHD
298 diagnostic criteria, especially when diagnosing headaches whose clinical features are
299 characteristic of more than one headache type.
185
300 In contrast to cervical articular impairment, measures of cervical muscle function and
301 behavior were not different between groups. These results contrast with results of previous
302 studies that showed these impairments to be present in CGH group but not in migraine and
303 control groups [10, 12, 34]. One reason for this difference may be the heterogeneity of our
304 non-migraine group, which comprised participants with predominant tension-type and/or
305 CGH, including 22 participants with comorbid migraine. The heterogeneity of the non-
306 migraine group could have diluted any difference in cervical musculoskeletal impairments
307 between headache types. Another possible explanation for the lack of significant difference in
308 cervical muscle impairment between headache groups may be due to the different
309 experimental protocols used. For example, the equipment we used for measuring strength was
310 different from those used in previous studies [10, 34]. We used a dynamometer which is often
311 available in clinics but may not have been as sensitive as the equipment used in previous
312 studies. This is the first cross-sectional study that evaluated the DCE test, to potentially
313 complement existing evidence on impairment in deep cervical flexors performance in CGH.
314 Given the lack of difference demonstrated between headache groups, examination of the
315 behavior of cervical extensors cannot be recommended at this point in time. In our
316 assessment using the exploratory DCE test using ultrasound imaging, we imaged the
317 extensor muscles at C4 level. Subsequent revised protocols of this test have demonstrated a
318 significant difference when the muscles were imaged higher to the proposed source of
319 symptoms in the spine, namely at C2 level [35].
320 Nevertheless, the finding that cervical muscle impairment was not significantly
321 different between migraine and non-migraine groups is worth noting and exploring further.
322 Despite the lack of statistically significant difference between groups, cervical spine joint and
323 muscle impairmentswere generally worse in non-migraine headache, consistent with our
186
324 hypothesis and previous studies [10, 34].Further work on cervical muscle impairment is
325 recommended, utilizing refined protocols and pure headache groups.
326 The results also demonstrated that people with migraine had significantly higher pain
327 ratings and disability scores than those with non-migraine headaches. While numerical rating
328 scales of pain intensity were able to distinguish headache types, SF-MPQ-2 and CSI did not
329 appear to do so, suggesting that multidimensional pain and central sensitization experience
330 may be similar in migraine and non-migraine headaches. We also did not find DASS-21
331 scores to be differentiators of headache types in this cohort, despite previous studies showing
332 an association of negative emotional states with high levels of pain and disability [36]. The
333 high pain rating and disability scores in migraine are consistent with previous studies [37]
334 and with the ICHD definition of migraine as a more intense headache [5]. These results are
335 also consistent with migraine ranking in the top ten disabling conditions globally and the
336 highest headache type on this list [3]. The high disability profile associated with migraine can
337 help distinguish it from non-migraine headaches. Factors that account for the higher disability
338 in migraine versus other headache types may be explored in prospective qualitative and
339 longitudinal cohort studies.
340 As well, the disability scores from self-report questionnaires had acceptable
341 discriminative ability. This raises a possible role for the use of these questionnaires in the
342 diagnostic workup of people with migraine.Of the disability questionnaires tested in this
343 study, HDI and HDQ appear to be the best questionnaires to use in distinguishing migraine
344 from non-migraine headaches. The diagnostic utility for both HDI and HDQ is promising,
345 given their AUC values on ROC curve analyses of 0.80 and 0.82, respectively. These AUC
346 values suggest that HDI and HDQ could be used to distinguish migraine from non-migraine
347 headaches. Both HDI and HDQ measure the severity of the interference of the headache with
348 daily activities and the presence of the emotional aspects of disability [27, 28]. Results of this
187
349 study therefore indicate that these aspects of disability measured by HDI and HDQ are better
350 differentiators of headaches than the frequency of interference of the headache with daily
351 activities measured by other disability questionnaires [29, 30] tested in this study.
352 When combined tests were considered, we found that a combination of no pain on
353 manual examination of the cervical spine, less change in cervical extensor thickness during
354 contraction,less frequent headaches, and higher self-reported disability distinguished
355 migraine from non-migraine headaches. These results support the combined assessment of
356 aspects of cervical joint function and muscle behavior together with a comprehensive
357 symptom and disability profile as being useful in differentiating migraine from non-migraine
358 headache. This combined assessment is easy to perform and is clinically feasible. Moreover,
359 this combined assessment could complement the presently used model of diagnosing
360 primarily based on headache features to characterize associated impairments and disability.
361 Further, the presence of cervical musculoskeletal impairmentin migraine, although less than
362 in non-migraine, and the disability and multidimensional pain profile in migraine may also
363 inform research directions for modifiable targets of alternative migraine interventions.
364
365 Conclusions
366 Less cervical musculoskeletal impairmentand higher pain and disability, when measured
367 independently,distinguished migraine from non-migraine headaches. A combination of these
368 characteristics and less frequent headaches distinguished migraine with acceptable sensitivity
369 and specificity. Results support the assessment of cervical musculoskeletal impairment and
370 patient-reported outcomes to better characterize and differentially diagnose migraine from
371 non-migraine headaches. Assessing these characteristics could complement diagnosis using
372 existing diagnostic criteria for migraine.
373
188
374 Abbreviations
375 AUC: area under the curve ; CGH: cervicogenic headache; CROM: Cervical Range of
376 Motion Instrument; CSI: Central Sensitization Inventory; DASS-21: Depression Anxiety
377 Stress Scales-2; DCE test: Deep cervical extensor test; HDI: Henry Ford Headache Disability
378 Inventory; HDQ: Headache Disability Questionnaire; HIT-6: Headache Impact Test-
379 6TM; ICHD: International Classification of Headache Disorders; IQR: interquartile range;
380 LSD: least significant difference; PAIVMs: passive accessory intervertebral movements;
381 ROC: receiver operating characteristic; SF-MPQ-2: Short-form McGill Pain Questionnaire-2;
382 TTH: tension-type headache; WHODAS: World Health Organization Disability Assessment
383 Schedule 2.0
384
385 Ethics approval and consent to participate
386 This research was granted ethics approval by the Human Research Ethics Committee of The
387 University of Sydney (Project Number 2014/536).All participants provided written informed
388 consent prior to participation.
389
390 Competing interests
391 All authors declare no competing interests.
392
393 Funding
394 This research received no specific grant from any funding agency in the public, commercial,
395 or not-for-profit sectors.
396 Maria-Eliza Aguila was supported by a fellowship through the Doctoral Studies Fund under
397 the Expanded Modernization Program of the University of the Philippines. Trudy Rebbeck
398 was supported by a fellowship from the Australian National Health and Medical Research
189
399 Council (NHMRC).
400
401 Authors’ contributions
402 MA, AL, TR conceived and designed the research. MA, SH, KA collected data. MA, AL,
403 TR, KN analysed and interpreted the data. All authors contributed with drafting and revising of
404 the manuscript and critical appraisal of its content. All authors approved the final manuscript.
405
406 Acknowledgements
407 We thank all the participants for their cooperation, and the staff of the Sydney Specialist
408 Physiotherapy Centre for their support during the conduct of this study. We also thank the
409 following for their help in recruiting participants: Headache Australia, Australian Pain
410 Society, Australian Pain Management Association, Painaustralia, the editorial team of Ang
411 Kalatas Australia, and Dr Craig Moore and the staff of Spinal Solution.
412 We also acknowledge Dr Jillian Clarke for her technical assistance with setting up the
413 parameters for real-time ultrasound imaging and Mr Ray Patton for his technical assistance
414 with the cervical extensor endurance test equipment.
415
190
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195
520 Table Legends
521 Table 1. Demographic characteristics of participants (n = 125)
522
523 Table 2. Headache characteristics of participants with recurrent headaches (n = 85)
524
525 Table 3. Comparison of performance on cervical musculoskeletal impairment tests between
526 participant groups (n = 125)
527
528 Table 4. Comparison of scores on self-report questionnaires between participant groups (n =
529 125)
530
531 Table 5. Discriminant function coefficients (standardized coefficients) for characteristics with
532 highest predictive ability for migraine
533
534 Table 6. The sensitivity and specificity of characteristics to categorize migraine from
535 participants with non-migraine headaches (n = 85)
536
196
537 Figure Legend
538 Figure 1. Flow of participants through the study
197
Figure 1.Flow of participants through the study
198
CHAPTER SIX
Six-Month Clinical Course and Factors Associated with
Non-Improvement in Migraine and Non-Migraine Headaches
Chapter Six is the peer reviewed version of the following article: Aguila ME, Rebbeck T,
Pope A, Ng K, Leaver AM. Six-month clinical course and factors associated with non-
improvement in migraine and non-migraine headaches, which has been accepted for
publication with revisions in Cephalalgia (16 June 2017).
199
As co-authors ofthe paper “Six-month clinical course and factors associated with non-
recovery in migraine and non-migraine headaches”, we confirm that Maria Eliza Ruiz Aguila
has madethe following contributions:
• Conception and design of theresearch
• Analysis and interpretation ofdata
Signed: Alun Pope Date: 31 March 2017
200
Manuscript Title: Six-Month Clinical Course and Factors Associated with Non-
Improvement in Migraine and Non-Migraine Headaches
Authors: Maria-Eliza R. Aguila, MPhysio1,2, Trudy Rebbeck, PhD1,3, Alun Pope, PhD4, Karl
Ng, PhD5, Andrew M. Leaver, PhD1
Authors’ Institutional Information:

1
2
3
4
Statistical Consulting, University of Sydney
Cleveland St, Darlington, New South Wales 2008 AUSTRALIA
5
201
[email protected]
202
Abstract:
Background: Evidence on medium-term clinical course of recurrent headaches is scarce. This
study explored the six-month course and factors associated with non-improvement in
migraine compared with tension-type headache and cervicogenic headache.
Methods: In this longitudinal cohort study, the six-month course of headaches was
prospectively examined in participants (n=37 with migraine; n=42 with tension-type or
cervicogenic headache). Participants underwent physical examination for cervical
musculoskeletal impairments at baseline. Participants also completed questionnaires on pain,
disability and other self-report measures at baseline and follow-up, and an electronic diary
for 6 months. Course of headaches was examined using mixed within-between analyses of
variance and Markov chain modeling. Multiple factors were evaluated as possible factors
associated with non-improvement using regression analysis.
Results: Headache frequency, intensity, and activity interference in migraine and non-
migraine headaches were generally stable over 6 months but showed month-to-month
variations. Day-to-day variations were more volatile in the migraine than the non-migraine
group, with the highest probability of transitioning from any headache state to no headache
(probability = 0.82–0.85). The odds of non-improvement in disability was nearly 6 times
higher with cervical joint dysfunction [odds ratio (95% CI) = 5.58 (1.14–27.42].
Conclusions: Headache frequency, intensity, and activity interference change over 6 months,
with day-to-day variation being more volatile in migraine than non-migraine headaches.
Cervical joint dysfunction appears to be associated with non-improvement for disability in 6
months. These results may contribute to strategies for educating patients to help align their
expectations with the nature of their headaches.
203
Key words: migraine, tension-type headache, cervicogenic headache, disability, longitudinal
study
204
Introduction
Migraine and other common recurrent headaches such as tension-type headache (TTH) and
cervicogenic headache (CGH) may present as episodic attacks, yet persist over time (1-3). To
date, knowledge of how these headaches change over time is not fully understood. Evidence
from a few longitudinal population-based and clinic-based studies has demonstrated the
variable clinical course of migraine and TTH, in particular, in the long term. Specifically,
migraine and TTH have been shown to remit in most people, follow a stable course in others,
and progress to higher frequency episodes or other poorer outcomes in a few (4-6). For those
cases in whom headaches progressed, the following have been identified as predictors: age at
onset younger than 20, female, low education and socioeconomic status, white people, head
injury, high attack frequency, obesity, medication overuse, stressful life events, caffeine
overuse, sleeping problems, and other pain syndromes (6-8). Correspondingly, predictors for
remission or recovery from headache have been identified, including less severe headaches at
baseline, absence of anxiety and of sleep problems (8), episodes not triggered by alcohol,
absence of associated symptoms (4), and short headache duration (5).
However, less is known about how recurrent headaches change and their associated
factors in the medium term, which is often considered more important to patients. One
longitudinal observational study has shown that clinical characteristics of migraine remain
stable over 3 months, with a general trend toward improvement in disability (9). Additionally,
improved disability had a moderate positive association with headache frequency in 3
months. Further evidence is required to build on these findings by identifying the short- to
medium-term variations in headaches. Specifically, information regarding day-to-day
variation in headaches will be relevant to patients with recurrent episodic headaches such as
migraine and non-migraine headaches that present frequently to primary care (TTH and
205
CGH). For many of these patients, daily function is disrupted even on non-headache days
because of the unpredictability of their headaches (10) despite undergoing treatment (9).
Knowledge of the medium-term course of common recurrent headaches such as
migraine, TTH and CGH will further characterize these headaches and, ultimately, contribute
to a greater understanding of their entire clinical course. By knowing the behavior of their
headaches in the medium term, patients could form realistic expectations accordingly, which,
in turn, could positively influence the way they manage their headaches and reduce their
disability. Characterization of migraine and non-migraine headaches could be further
broadened when physical impairments that have been reported to be present and treated in
these headaches, such as cervical musculoskeletal impairments (11-14), are considered. For
example, upper cervical joint dysfunction, as conceivably suggested by the presence of light-
headedness, was associated with poor outcome in CGH after one year of active treatment
(15). This might be the case for migraine as well; however, this has not been demonstrated.
Understanding which factors are associated with poorer short- or medium-term outcomes
could assist in mediating or managing these factors toward a more favorable clinical course
(7).
Therefore, the primary aim of this study was to describe and compare the medium-
term clinical course of migraine and non-migraine headaches in terms of headache frequency,
intensity, and activity interference. A secondary aim was to explore factors that are associated
with non-improvement in perceived disability, headache frequency and intensity in the
medium-term.
Methods
Design
In this longitudinal observational cohort study, we investigated the clinical course of different
206
headache types and factors that predicted this clinical course by following groups of people
with migraine and non-migraine headaches for a period of 6 months. This research was
granted ethics approval by the Human Research Ethics Committee of The University of
Sydney (Project Number 2014/536).
Participants
We recruited volunteers aged 18 to 65 with recurrent headache through advertisements posted
at community bulletins, social media, and primary and specialist care clinics. Participants
were included if they had headaches for at least one year and had at least one headache
episode in the previous month. Participants were excluded if they had known secondary
headache classifications (e.g. tumor, substance withdrawal etc.) or psychiatric disorders.
Participants were then classified into the migraine group (fulfilling the criteria for migraine
only and not those for other headache types) or non-migraine group (with primary diagnosis
of TTH and/or CGH, with or without comorbid migraine) using the ICHD-3 beta criteria
(14).
Procedure
All participants underwent initial telephone screening to confirm their eligibility. All eligible
participants provided written informed consent prior to participation. Eligible participants
then completed questionnaires at baseline regarding demographic and headache
characteristics, as well as patient-reported outcomes such as multidimensional pain,
disability, and other health measures. Multidimensional pain and disability assessment
included the Short-form McGill Pain Questionnaire-2 (SF-MPQ-2) (16), Central Sensitization
Inventory (CSI) (17), Henry Ford Headache Disability Inventory (HDI) (18), Headache
Disability Questionnaire (HDQ) (19), Headache Impact Test-6TM (HIT-6) (20), and World
207
Health Organization Disability Assessment Schedule 2.0 (WHODAS) (21). Other health
measures comprised those previously shown to predict long-term course of headaches. These
included the Depression Anxiety Stress Scales-21 (DASS-21) (22) to assess negative
emotional states, the Self-Administered Comorbidity Questionnaire (SCQ) (23) to assess
comorbidities (4), the Pittsburgh Sleep Quality Index (PSQI) (24) to assess sleep (6), and the
International Physical Activity Questionnaire (IPAQ) (25) to measure physical activity (4).
Participants then attended one assessment for interview and physical examination, in
which headaches were classified and data for cervical musculoskeletal impairments were
collected. Headache classification used ICHD-3 beta criteria (14) independently done by two
researchers. Cervical musculoskeletal impairment data comprised joint dysfunction and
cervical muscle behavior. These impairments were shown to be different between migraine
and non-migraine headache groups in our previous cross-sectional work. Joint dysfunction
was assessed through manual examination of the upper cervical spine with passive accessory
intervertebral movements (PAIVMs) (26) and the flexion-rotation test (27). Manual
examination of the cervical spine was deemed positive if headache was provoked. The
flexion rotation test was deemed positive if headache was provoked and the range of
movement was ≤ 32°. Cervical muscle behavior was assessed using the extensor under load
test, a new technique that measures changes in thickness of the deep cervical extensor during
low-load using ultrasound imaging (28).
Participants then filled out an electronic diary daily for 6 months, beginning the day
after their physical examination. Participants recorded the presence of headaches daily and
provided information on headache intensity using the numerical rating scale (NRS: with
anchors at 0 and 10: 0 = no headache, 10 = worst headache possible), and interference of the
headache with normal daily activities on a scale of not at all (0), a little bit (1), moderately
(2), quite a bit (3), and extremely (4). The diary was administered and data were collected
208
and managed using the Research Electronic Data Capture (REDCap) application (Research
Electronic Data Capture, Nashville, Tennessee, USA) (29) hosted at The University of
Sydney. Participants also completed the pain and disability questionnaires at 1 month, 3
months, and 6 months after their physical examination.
Statistical Analysis
The sample size of the present study was based on the sample size of our previous cross-
sectional study (currently under review) (n = 40 per group). This sample size was powered to
detect group differences in cervical musculoskeletal impairments, which was the focus of the
cross-sectional study.
Distributions of data were examined through visual inspection by a statistician and
using the Shapiro-Wilk test. Accordingly, demographic and headache characteristics, and
questionnaire scores were summarized as mean and standard deviation (SD). Additionally,
baseline clinical characteristics between the migraine and non-migraine groups were
compared using Student t test, (for continuous variables) or Chi square test (for categorical
variables). The month-to-month variation in the clinical course of headaches over 6 months
and between-group comparisons were examined using mixed within-between analyses of
variance (ANOVA). The day-to-day variation in clinical course of headaches over 6 months
was examined using Markov chain modeling (30). Details of the day-to-day variations
derived from Markov chain modeling included the probabilities of transitioning from a given
headache intensity and activity interference state to another or the same state on the next day.
This approach models the randomness in headache behavior. For Markov chain modeling,
intensity was described as ‘no headache’ (NRS 0/10), ‘mild’ (NRS 1–3/10), ‘moderate’ (NRS
4–6/10), or ‘severe’ (NRS ≥ 7/10) to simplify the categories. Markov chain modeling also
generated simulated models of the clinical course of headache intensity and activity
209
interference in 30 days in hypothetical individuals with headaches.
The relationship between the dependent variable, absence of clinically meaningful
improvement (i.e., non-improvement of headaches) and independent variables, namely
demographic and headache characteristics, cervical musculoskeletal impairments, and scores
on multidimensional pain, disability, and other health measures were explored using logistic
regression analyses. In the absence of a standard definition of non-improvement of
headaches, we defined the primary dependent variable, for the purpose of regression
analyses, to be < 2.5 point reduction in HIT-6 scores (disability) (31). Secondary dependent
variables were < 50% reduction in headache frequency (32) and < 15% reduction in headache
intensity (33). The relationship between dependent and independent variables was initially
explored using univariate logistic regression analyses. Independent variables with p < 0.2
based on the Wald Chi square statistic on univariate analyses were entered into multiple
regression analyses using the ‘enter’ method. In all analyses, headache group was added as an
independent variable. Dependent variables were presented as short-term changes (Month 3
minus Month 1) and medium-term changes (Month 6 minus Month 1). Month 1 was
considered as the baseline for the change scores in dependent variables; this allowed
collection of prospective data from the headache diary for 1 month to serve as baseline data
for headache characteristics.
Statistical analyses were conducted using R studio version 3.3.0 2016 (R Foundation
for Statistical Computing, Vienna, Austria) and Statistical Package for Social Sciences®
Significance level for statistical analyses other than univariate logistic regression was set at
0.05.
Results
210
Participants
Forty people with migraine and 45 people with non-migraine headache [mean age (standard
deviation) = 37.15 (12.88) years] participated in this study. The flow of participants through
the study and reasons for exclusion from analyses are shown in Figure 1. Demographic,
headache and clinical characteristics of participants at baseline are presented in Table 1. The
migraine group had longer history of headache [mean (SD) 20.44 (12.90) years versus 13.44
(12.76) years; p = 0.014], less frequent headaches in a month [4.93 (5.89) versus 9.74 (7.66);
p = 0.002], and higher average headache intensity per month [6.46 (1.65) versus5.57 (1.64); p
= 0.014] than the non-migraine group. More participants in the migraine group were taking
triptan than the non-migraine group [n (%) 19 (47.50%) versus 10 (22.22%) participants; p =
0.014]. Fewer participants in the migraine group had cervical musculoskeletal impairments
than the non-migraine group. For example, 4 (10.00%) participants from the migraine group
reported pain on manual examination of the upper cervical joints compared to 26 (57.78%)
participants from the non-migraine group.
Clinical course of migraine and non-migraine headaches
Headache characteristics changed over 6 months for both headache groups without fully
remitting nor progressing (Figure 2). Headache frequency fluctuated from month to month in
both headache groups (Figure 2A; p = 0.001), with the migraine group showing more
fluctuations than the non-migraine group (p = 0.005). The migraine group consistently had
fewer headaches per month than the non-migraine group.
Average headache intensity fluctuated from month to month over 6 months for both
headache groups (Figure 2B; p = 0.042), but this fluctuation was not significantly different
between the two headache groups (p = 0.94). Average headache intensity oscillated around
NRS 4/10 (moderate intensity) for both groups. Considering day-to-day fluctuation in
211
headache intensity, Markov chain analysis showed that every headache intensity state could
be reached from any headache intensity state for both headache groups (Figure 3). The day-
to-day transition between headache intensity states of the migraine group ranged from a
probability of 0.02 (from mild headache to severe headache the next day) to 0.82 (from no
headache to remaining without headache the next day) (Figure 3A).
In contrast, the day-to-day transition between headache intensity states of the non-
migraine group ranged from a probability of 0.04 (from no or mild headache to severe
headache the next day) to 0.76 (from no headache to remaining without headache the next
day) (Figure 3B). The migraine group generally had the greatest probabilities of transition
from any headache state to no headache. The transition probabilities for headache intensity
differed significantly between the headache groups (p < 0.001), with the migraine group
showing more volatility. Based on the transition probabilities, any headache intensity would
have higher probabilities to have no headache the following day in migraine. In contrast, any
headache intensity would have higher probabilities of staying the same or having no
headache the following day in non-migraine headaches. The day-to-day volatility of headache
intensity in the migraine group was highlighted when modeled using Markov chains (Figure
4).
Average activity interference caused by headaches fluctuated from month to month
for both headache groups (Figure 2C; p = 0.002) but this fluctuation was not significantly
different between the two headache groups (p = 0.12). The activity interference for both
groups oscillated around NRS 1.5 / 4 (headaches interfered a little bit to moderately with
normal daily activities). Considering the day-to-day fluctuation in activity interference,
Markov chain modeling showed that every interference state could be reached from any
interference state for both headache groups (Figure 5). The day-to-day transition between
activity interference states of the migraine group ranged from a probability of 0.01 (from no
212
interference to extreme interference) to 0.85 (from no interference to remaining without
interference) (Figure 5A). In contrast, the day-to-day transition between activity interference
states of the non-migraine group ranged from 0.01 (from no interference to extreme
interference the next day) to 0.81 (from no interference to remaining without interference the
next day) (Figure 5B). The migraine group generally had the greatest probabilities of
transition from any interference state to no interference. The transition probabilities for
activity interference differed significantly between the headache groups (p < 0.001). The day-
to-day fluctuation in activity interference was highlighted by simulation models derived from
Markov chain analysis (Figure 6).
Factors associated with non-improvement of migraine and non-migraine headaches as to
headache-related disability, headache frequency and intensity
The univariate analysis revealed that receiving physical treatment, pain and disability at
baseline, and physical activity level were independently associated with non-improvement in
headache disability in the short-term (Table 2) and headache intensity, pain, disability scores
and physical activity level were associated with non-recovery in the medium term (Table 3).
Multifactorial models were associated with non-improvement in headache-related
disability at short- and medium-term. The full model containing migraine headache group,
receiving physical treatment, pain on manual examination of the upper cervical joints, higher
scores on disability questionnaires (namely HIT-6, HDQ and WHODAS), and lower level of
physical activity was statistically significant for predicting non-improvement in headache-
related disability at short-term (p = 0.040) and explained 27.7% of the variation in disability
(Table 4). However, no independent variable made a unique statistically significant
contribution to this model. Likewise, the full model containing headache group, age, average
headache intensity, average activity interference, pain on manual examination of the upper
213
cervical joints, scores on disability questionnaires (namely HIT-6, HDQ and WHODAS), and
level of physical activity was statistically significant for predicting non-improvement in
headache-related disability at medium-term (p = 0.031) and explained 32.3 % of the variation
in disability (Table 5). Of these predictors, pain on manual examination of the upper cervical
joints made a statistically significant contribution to this model (p = 0.034). Specifically, the
odds of non-improvement in disability was nearly 6 times higher when pain on manual
examination was present than when it was absent [odds ratio (95% CI) = 5.58 (1.14–27.42].
In contrast, none of the variables examined in this study were associated with non-
improvement in headache frequency or intensity after 3 or 6 months (Tables 2–5).
Discussion
This study demonstrated three main findings on the 6-month clinical course and factors
associated with outcome in migraine and non-migraine headaches. First, the clinical course of
headache characteristics in migraine and non-migraine headaches showed month-to-month
variability, but generally did not remit nor progress. Second, day-to-day variations in
headache intensity and activity interference were more volatile in the migraine group than the
non-migraine group. Third, a number of demographic, clinical and patient-related factors
were associated with persistent disability over 3 and 6 months. These findings further
characterize and differentiate migraine and non-migraine headaches, thus informing clinical
practice and research.
The month-to-month variation in headache frequency, intensity, and activity
interference in migraine and non-migraine headaches changed, but did not fully remit nor
progress. These results are consistent with existing evidence for the 3-month clinical course
of migraine (9) and show a similar trend as the prevailing knowledge on the long-term
clinical course of changes in migraine (4, 34). Headache intensity fluctuated around moderate
214
intensity for both headache groups, challenging the typical picture of migraine as a more
severe headache than non-migraine headaches (14). Analogously, activity interference caused
by headaches over 6 months hovered between little to moderate interference for both
headache groups. This range of activity interference contrasts with the high levels of
disability associated especially with migraine and TTH (35). On closer consideration, such
disparities in intensity and activity limitation ratings are understandable and may be partly
attributed to measuring intensity and activity interference prospectively using a headache
diary. First, retrospective rating by patients tends to overestimate headache intensities
compared with information from diaries (36). Second, the perceived impact of the headache
on daily activities measured each day could be lower compared to perceived disability over
extended periods as captured by self-report questionnaires.
This study also presents new evidence that characterizes the day-to-day variation in
headache intensity and activity interference as being more volatile in migraine than in non-
migraine headaches. This greater volatility in migraine, as demonstrated by Markov chain
analyses, is related to the higher probability of having no headache on the following day
regardless of the current headache state. Further, the different possible scenarios of
transitioning between headache states imply that the extent of volatility may be different
between individuals with similar headache diagnoses, undergoing their usual treatment, and
having the same level of headache intensity and activity interference on a particular day.
This study also presents preliminary evidence that factors influencing non-
improvement in disability in 6 months include headache features, cervical joint dysfunction,
disability and physical activity. This preliminary evidence presents prospective directions for
future research. Of note is cervical joint dysfunction which appears to be associated with non-
improvement in disability in both migraine and non-migraine groups yet was less frequent in
the former (10.00% versus 57.78%). The lack of factors significantly associated with non-
215
improvement in frequency and intensity may most likely be indicative that no factor
significantly influences those outcomes in the short-to medium-term. The same can be said
for non-improvement in disability in the short-term. However, the multifactorial model for
disability explains 27.7% and 32.3% of the variability in the model in the short- and medium-
term, respectively. The association of these factors with disability needs to be further
investigated in larger cohort studies with pure headache groups. Prospective studies may also
explore other factors that would influence non-improvement in disability.
Results of this study inform headache management. First, information about the
month-to-month and day-to-day variation in features of migraine and non-migraine
headaches can form part of patient education. Importantly, educating patients about the most
likely behavior of their headaches will help them align their expectations. This information
could also be reassuring for patients who perceive the unpredictability of their headaches as
disabling and disquieting (10, 37). Second, the small but statistically significant month-to-
month variation in headache characteristics over 6 months justifies continued monitoring of
symptoms as part of headache management. Third, the association of cervical joint
dysfunction with non-improvement in headache-related disability in 6 months reveals the
usefulness of cervical joint assessment and, if necessary, targeting any impairments to help
reduce disability in the short- to medium-term.
The study aimed to describe the shorter-term clinical course of migraine and non-
migraine headaches with participants having their usual headache management, when
interventions were not standardized. As such, we did not control for intervention and other
possible confounding factors that could influence the course of headaches. Prospective
clinical trials are indicated to investigate those other factors to build on evidence from this
study. Such trials can also use evidence presented here concerning the 6-month clinical
course of migraine and non-migraine headaches when selecting outcome measures. Further
216
studies involving pure headache groups and collecting longitudinal data on possible variables
influencing non-improvement are also required to validate our results. Investigating the
underlying mechanisms explaining the difference in month-to-month and day-to-day
variation between migraine and non-migraine headaches also remains an area for future
investigation.
In conclusion, headache frequency, intensity, and activity interference show month-
to-month and day-to-day variations over 6 months in individuals with migraine and non-
migraine headaches who are already receiving treatment. Day-to-day variations in headache
intensity and activity interference are more volatile in migraine compared with non-migraine
headaches. Cervical joint dysfunction measured using manual examination appears to be
associated with non-improvement in headache-related disability in 6 months. These results
will contribute to strategies for patient education regarding the nature of their headaches, and
also carry implications for outcome measure selection in prospective clinical trials.
217
Conflict of Interest Statement: All authors declare no conflicts of interest.
Acknowledgements:
This research received no specific grant from any funding agency in the public, commercial,
or not-for-profit sectors.
We thank all the participants for their cooperation, and the staff of the Sydney Specialist
Physiotherapy Centre for their support during the conduct of this study. We also thank the
following for their help in recruiting participants: Headache Australia, Australian Pain
Society, Australian Pain Management Association, Painaustralia, the editorial team of Ang
Kalatas Australia, and Dr Craig Moore and the staff of Spinal Solution.
We also acknowledge Dr Jillian Clarke for her technical assistance with setting up the
parameters for real-time ultrasound imaging.
Maria-Eliza Aguila was supported by a fellowship through the Doctoral Studies Fund under
the Expanded Modernization Program of the University of the Philippines. Trudy Rebbeck
was supported by a fellowship from the Australian National Health and Medical Research
Council (NHMRC).
218
Clinical Implications:
• Headache frequency, intensity and activity interference show variations over 6 months,
but generally do not fully remit nor progress, in individuals with migraine and non-
migraine headaches.
• Day-to-day variation in headache intensity and activity interference is more volatile in
migraine than non-migraine headaches.
• Individuals with migraine or non-migraine headaches who have cervical spine
dysfunction are nearly 6 times more likely not to recover in terms of headache-related
disability within 6 months.
• These results contribute to strategies for educating patients on the nature of their
headaches.
• The need to consider volatility of headache characteristics when selecting outcome
measures for prospective clinical trials is highlighted.
219
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Figure Legends
Figure 1. Flow of participants through the study
Figure 2. Month-to-month variation in headache characteristics in migraine and non-migraine
groups. (A) Frequency of headaches. (B) Average headache intensity. (C) Average
activity interference due to headache
Figure 3. Transition matrices of headache intensity showing the probability of transitioning
from a current headache intensity state (denoted by rows) to the next-day headache
intensity state (denoted by columns). (A) Migraine group. (B) Non-migraine group
(p < 0.001)
Figure 4. Simulated day-to-day clinical course of headache intensity of 12 hypothetical
individuals with headaches over 30 days (numerical rating scale; 0, no headache, to
3, severe headache. (A) Migraine group. (B) Non-migraine group (p < 0.001)
Figure 5. Transition matrices of activity interference caused by headache for migraine group
showing the probability of transitioning from a current activity interference state
(denoted by rows) to the next-day activity interference state (denoted by columns).
(A) Migraine group. (B) Non-migraine group (p < 0.001)
224
Figure 6. Simulated day-to-day clinical course of activity interference of 12 hypothetical
individuals with headaches over 30 days (activity interference rated using a scale;
0, not at all, to 4, extremely. (A) Migraine group. (B) Non-migraine group (p <
0.001)
225
Table Legends
Table 1. Baseline characteristics of participants [mean (SD) or n (%) where indicated] (n =
85)
Table 2. Univariate logistic regression analysis showing relationships between possible
factors associated with non-improvement in headache characteristics in the
SHORT-TERM
Table 3. Univariate logistic regression analysis showing relationships between possible
factors associated with non-improvement in headache characteristics in the
MEDIUM-TERM
Table 4. Multivariate logistic regression predicting likelihood of non-improvement in
headache characteristics in the SHORT-TERM
Table 5. Multivariate logistic regression predicting likelihood of non-improvement in
headache characteristics in the MEDIUM-TERM
226
Enrolment
Assessed for eligibility (n=134)
Excluded: (n=45)
♦ Did not meetinclusion criteria (n=12)
♦ Unavailable for physical examination
(n=33)
Withdrew consent prior to formal

enrolment in study (n=4)
Found eligible, enrolled and underwent

interview and physical examination (n=85)
Allocation
Classified into migraine group (n=40) Classified into non-migraine group (n=45)
Follow-Up
Had headache Completed follow- Had headache Completed follow-
diary entries until up questionnaires: diary entries until up questionnaires:
Month 6: n=37 n=33 Month 6: n=42 n=35
• Lost to follow • Lost to follow • Lost to follow • Lost to follow
up (n=3) up(n=7) up (n=3) up(n=10)
Analysis
Analyzed for Analyzed for Analyzed for Analyzed for
clinical course of factors associated clinical course of factors associated
migraine with clinical non-migraine with clinical
course of migraine headaches course of non-
migraine
(n=37) (n=33) (n=42) (n=35)
Figure 1. Flow of participants through the study
227
Figure 2.Month-to-month variation in headache characteristics in migraine and non-migraine groups. (A) Frequency of headaches. (B) Average
headache intensity. (C) Average activity interference due to headache
228
A
Initial State of
Subsequent State of Headache Intensity
Headache Intensity
No Headache Mild Moderate Severe
No Headache 0.82 0.09 0.06 0.03

Mild 0.61 0.25 0.12 0.02
Moderate 0.48 0.15 0.21 0.16
Severe 0.36 0.06 0.26 0.32
Initial State of
Subsequent State of Headache Intensity
Headache Intensity
No Headache Mild Moderate Severe
No Headache 0.76 0.11 0.09 0.04

Mild 0.45 0.37 0.14 0.04
Moderate 0.36 0.20 0.31 0.13
Severe 0.24 0.11 0.26 0.39
Figure 3.Transition matrices of headache intensity showing the probability of transitioning from a current
headache intensity state, denoted by rows, to the next-dayheadache intensity state, denoted by
columns. (A) Migraine group. (B) Non-migraine group(p< 0.001)
229
A
(numerical rating scale 0-4)
Headache Intensity
B
Headache Intensity
Figure 4.Simulated day-to-day clinical course of headache intensity of 12 hypothetical individuals with
headaches over 30 days (numerical rating scale a scale; 0, no headache,to 3, severe headache.
(A) Migraine group. (B) Non-migraine group (p < 0.001)
230
A
Initial State of
Activity
Interference Subsequent State of Activity Interference Caused by Headache
Caused by
Headache
Not at All A Little Bit Moderately Quite a Bit Extremely
Not at All 0.85 0.08 0.04 0.02 0.01
A Little Bit 0.63 0.18 0.12 0.06 0.01
Moderately 0.46 0.22 0.22 0.08 0.02
Quite a Bit 0.43 0.14 0.22 0.17 0.04
Extremely 0.44 0.10 0.10 0.13 0.23
Initial State of
Activity
Interference Subsequent State of Activity Interference Caused by Headache
Caused by
Headache
Not at All A Little Bit Moderately Quite a Bit Extremely
Not at All 0.81 0.12 0.04 0.02 0.01
A Little Bit 0.52 0.28 0.13 0.05 0.02
Moderately 0.38 0.28 0.20 0.11 0.03
Quite a Bit 0.31 0.19 0.19 0.24 0.07
Extremely 0.26 0.15 0.12 0.20 0.27
Figure 5. Transition matrices of activity interference caused by headache for migraine group showing the
probability of transitioning from a current activity interference state, denoted by rows, to the next-
day activity interference state, denoted by columns. (A) Migraine group. (B) Non-migraine group
231
(numerical rating scale 0-4) A
Activity Interference
B
Activity Interference
Figure 6.Simulated day-to-day clinical course of activity interference of 12hypothetical individuals with
headaches over 30 days (activity interference rated using a scale; 0, not at all, to 4, extremely. (A)
Migraine group. (B) Non-migraine group (p < 0.001) 232

Table 1. Baseline characteristics of participants [mean (SD) or n (%) where indicated)] (n = 85)
Migraine Non-Migraine p values *

(n = 40) (n = 45)
Age 40.83 (12.87) 33.89 (12.11) 0.013
Gender (female) (n, %) 32 (80.00%) 40 (88.89%) 0.26
Body mass index 24.81 (4.93) 24.34 (5.83) 0.70
Headache characteristics
History of headache (years since first 20.44 (12.90) 13.44 (12.76) 0.014
episode)
Frequency of headache in a month 4.93 (5.89) 9.74 (7.66) 0.002
Episode duration, minimum (hours) 12.45 (16.00) 13.28 (17.61) 0.82
Episode duration, maximum (hours) 58.30 (35.69) 84.97 (168.60) 0.31
Average headache intensity per month 6.46 (1.65) 5.57 (1.64) 0.014
(0–10)†
Clinical characteristics
Receiving pharmacologic treatment (n,
%)
Paracetamol 14 (35.00%) 17 (37.78%) 0.79
Non-steroidal anti-inflammatory 18 (45.00%) 20 (44.44%) 0.96
drug
Tricyclic antidepressant 6 (15.00%) 3 (6.67%) 0.21
Triptan 19 (47.50%) 10 (22.22%) 0.014
Botulinum toxin 8 (20.00%) 11 (24.44%) 0.62
Beta blocker 4 (10.00%) 3 (6.67%) 0.58
Selective serotonin reuptake 5 (12.50%) 6 (13.33%) 0.91
inhibitor
Proton pump inhibitor 4 (10.00%) 6 (13.33%) 0.63
Anticonvulsant 5 (12.50%) 7 (15.56%) 0.69
Receiving physical treatment (n, %) 8 (20.00%) 12 (26.70%) 0.47
Pain on manual examination of the 4 (10.00%) 26 (57.78%) <0.001
upper cervical joints (n, %)
Positive flexion rotation test (n, %) 4 (10.00%) 17 (37.78%) 0.003
Extensor under load test (percent 6.17 (8.16) 11.87 (15.34) 0.035
change on symptomatic side)
NOTE. Bold numbers indicate statistical significance (p < 0.05)
*
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p values for Student t-test for continuous variables; p values for Chi-square test for categorical variables
†
Headache intensity: Numerical rating scale 0–10; 0 = no pain, 10 = worst possible pain
Table 2. Univariate logistic regression analysis showing relationships between possible predictors of non-
improvement in headache characteristics in the SHORT-TERM
HIT-6 Headache Frequency Headache Intensity
Nagelkerke p value Nagelkerke p value Nagelkerke p value

Variable R2 R2 R2
Age 0.011 0.46 0.037 0.196 0.019 0.38
Sex 0.002 0.78 0.003 0.70 0.001 0.80
BMI 0.001 0.86 0.143 0.035 0.042 0.24
Receiving pharmacologic 0.013 0.42 0.017 0.36 0.003 0.73
treatment
Receiving physical treatment 0.066 0.11 0.020 0.35 0.015 0.45
Frequency in a month 0.003 0.72 0.007 0.57 0.006 0.62
Average headache intensity last 0.008 0.54 0.036 0.20 0.065 0.10
month
Average activity interference 0.000 0.90 0.000 0.90 0.000 0.98
Pain on manual examination of the 0.043 0.17 0.005 0.62 0.000 0.89
upper cervical joints
Positive flexion rotation test 0.001 0.86 0.007 0.55 0.004 0.70
Percent change on symptomatic 0.000 0.91 0.019 0.39 0.004 0.68
side on extensor under load
test
SF-MPQ-2 Total score 0.004 0.65 0.000 0.91 0.000 0.90
CSI Total score 0.011 0.46 0.059 0.11 0.008 0.55
Disability
HIT-6 Score at baseline 0.114 0.028 0.019 0.35 0.000 0.97
HDI Total Score at baseline 0.012 0.45 0.025 0.29 0.003 0.71
HDQ Total Score at baseline 0.109 0.025 0.038 0.19 0.001 0.85
WHODAS Overall Score at 0.113 0.029 0.175 0.018 0.014 0.42
baseline
Emotional state
DASS-21 Depression Score 0.021 0.33 0.006 0.625 0.007 0.61
DASS-21 Anxiety Score 0.015 0.39 0.005 0.633 0.004 0.71
DASS-21 Stress Score 0.013 0.45 0.064 0.106 0.001 0.85
Other health measures
SCQ Overall Score 0.013 0.44 0.029 0.277 0.000 0.95
PSQI Total Score 0.011 0.47 0.010 0.496 0.027 0.28
Physical activity level 0.058 0.099 0.025 0.289 0.000 0.94
_____________________
Abbreviations: BMI, body mass index; CSI, Central Sensitization Inventory; DASS-21, Depression Anxiety Stress Scales-21; HDI, The Henry
Ford Headache Disability Inventory; HDQ, Headache Disability Questionnaire; HIT-6, Headache Impact Test-6; PSQI, Pittsburgh Sleep Quality
Index; SCQ, the Self-Administered Comorbidity Questionnaire; SF-MPQ-2, Short-form McGill Pain Questionnaire-2; WHODAS, World Health
Organization Disability Assessment Schedule
Bold numbers indicate possible predictors with p < 0.2
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Table 3. Univariate logistic regression analysis showing relationships between possible predictors of non-
improvement in headache characteristics in the MEDIUM-TERM
HIT-6 Headache Frequency Headache Intensity
Nagelkerke p value Nagelkerke p value Nagelkerke p value

Variable R2 R2 R2
Age 0.040 0.17 0.002 0.79 0.067 0.09
Sex 0.001 0.82 0.001 0.84 0.040 0.22
BMI 0.009 0.53 0.041 0.23 0.109 0.06
Receiving pharmacologic 0.005 0.64 0.026 0.26 0.000 0.96
treatment
Receiving physical treatment 0.026 0.27 0.010 0.51 0.001 0.85
Frequency in a month 0.001 0.85 0.004 0.68 0.067 0.09
Average headache intensity last 0.070 0.07 0.068 0.09 0.016 0.38
month
Average activity interference 0.052 0.11 0.008 0.56 0.001 0.82
Neck impairments
Pain on manual examination of the 0.057 0.10 0.017 0.37 0.002 0.76
Positive flexion rotation test 0.017 0.36 0.510 0.12 0.004 0.67
Percent change on symptomatic 0.007 0.55 0.012 0.50 0.000 0.99
side on extensor under load
test
SF-MPQ-2 Total score 0.002 0.76 0.022 0.34 0.018 0.37
CSI Total score 0.000 0.92 0.005 0.65 0.051 0.13
Disability
HIT-6 Score at baseline 0.049 0.13 0.011 0.48 0.029 0.24
HDI Total Score at baseline 0.001 0.83 0.000 0.97 0.087 0.06
HDQ Total Score at baseline 0.104 0.026 0.015 0.42 0.008 0.55
WHODAS Overall Score at 0.040 0.17 0.004 0.69 0.059 0.13
baseline
Emotional state
DASS-21 Depression Score 0.005 0.61 0.012 0.50 0.035 0.27
DASS-21 Anxiety Score 0.018 0.36 0.002 0.74 0.010 0.52
DASS-21 Stress Score 0.030 0.24 0.003 0.72 0.079 0.07
Other health measures
SCQ Overall Score 0.014 0.42 0.005 0.61 0.005 0.62
PSQI Total Score 0.000 0.89 0.013 0.43 0.009 0.53
Physical activity level 0.078 0.05 0.007 0.57 0.004 0.65
_____________________
Abbreviations: BMI, body mass index; CSI, Central Sensitization Inventory; DASS-21, Depression Anxiety Stress Scales-21; HDI, The Henry
Ford Headache Disability Inventory; HDQ, Headache Disability Questionnaire; HIT-6, Headache Impact Test-6; PSQI, Pittsburgh Sleep Quality
Index; SCQ, the Self-Administered Comorbidity Questionnaire; SF-MPQ-2, Short-form McGill Pain Questionnaire-2; WHODAS, World Health
Organization Disability Assessment Schedule 2.0
Bold numbers indicate possible predictors with p < 0.2
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Table 4. Multivariate logistic regression predicting likelihood of non-improvement in headache
characteristics in the SHORT-TERM
Outcome Predictor variables B (SE) Wald test p value OR (95% CI)
Headache Headache group 0.36 (0.81) 0.20 0.66 1.44 (0.29–7.08)

frequency
Age 0.03 (0.03) 0.77 0.38 1.03 (0.97–1.09)
BMI 0.17 (0.11) 2.42 0.12 1.18 (0.96–1.46)
CSI Total Score -0.04 (0.04) 1.17 0.28 0.96 (0.89–1.03)
HDQ Total Score 0.004 (0.03) 0.03 0.87 1.00 (0.95–1.06)
WHODAS Overall Score 0.10 (0.06) 2.45 0.12 1.10 (0.98–1.25)
DASS-21 Stress Score 0.05 (0.12) 0.19 0.66 1.05 (0.84–1.33)
Chi square 12.96, p = 0.07; Nagelkerke R2: 0.273
HIT-6 Headache group -0.68 (0.72) 0.89 0.34 0.51 (0.12–2.08)

score
Receiving physical treatment 1.63 (0.89) 3.36 0.07 5.10 (0.89–29.09)
Pain on manual examination of the

1.23 (0.81) 2.30 0.13 3.43 (0.70–16.90)
HIT-6 Score at baseline -0.06 (0.07) 0.65 0.42 0.94 (0.81–1.09)
HDQ Total Score at baseline -0.01 (0.03) 0.03 0.87 1.00 (0.94–1.06)
WHODAS Overall Score at baseline -0.02 (0.03) 0.52 0.47 0.98 (0.92–1.04)
Physical activity level at baseline 0.72 (0.51) 2.01 0.16 2.05 (0.76–5.55)

intensity
Average headache intensity -0.34 (0.20) 2.75 0.10 0.71 (0.48–1.06)
_____________________
Abbreviations: BMI, body mass index; CSI, Central Sensitization Inventory; DASS-21, Depression Anxiety Stress Scales-21; HDQ, Headache
Disability Questionnaire; HIT-6, Headache Impact Test-6; WHODAS, World Health Organization Disability Assessment Schedule 2.0
Bold numbers indicate statistical significance (p < 0.05)
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Table 5. Multivariate logistic regression predicting likelihood of non-improvement in headache
characteristics in the MEDIUM-TERM
Outcome Predictor variables B (SE) Wald test p value OR (95% CI)

frequency
Average headache intensity 0.31 (0.19) 2.63 0.11 1.36 (0.94–1.97)
Positive flexion rotation test -0.97 (0.66) 2.18 0.14 0.38 (0.10–1.38)
Chi square 5.37 p = 0.15; Nagelkerke R2: 0.112
HIT-6 Headache group -0.59 (0.70) 0.72 0.40 0.55 (0.14–2.16)

score
Age 0.05 (0.03) 3.65 0.06 1.05 (1.00–1.11)
Average headache intensity -0.14 (0.26) 0.29 0.59 0.87 (0.52–1.45)
Average activity interference -0.28 (0.69) 0.16 0.69 0.76 (0.20–2.92)
Pain on manual examination of the

1.72 (0.81) 4.48 0.034 5.58 (1.14–27.42)
HIT-6 Score at baseline 0.01 (0.07) 0.02 0.89 1.01 (0.87–1.17)
HDQ Total Score at baseline -0.04 (0.04) 1.31 0.25 0.96 (0.90–1.03)
WHODAS Overall Score at baseline 0.02 (0.03) 0.43 0.51 1.02 (0.96–1.09)
Physical activity level 1.06 (0.56) 3.64 0.06 2.89 (0.97–8.61)
Headache Headache group -0.004 (0.76) 0.00 1.00 1.00 (0.23–4.41)

intensity
Age 0.03 (0.03) 0.63 0.43 1.03 (0.96–1.09)
BMI 0.10 (0.09) 1.11 0.29 1.10 (0.92–1.32)
Frequency of headaches 0.09 (0.06) 2.28 0.13 1.10 (0.97–1.24)
CSI Total Score -0.04 (0.03) 1.11 0.29 0.96 (0.90–1.03)
HDI Total Score 0.02 (0.02) 0.69 0.41 1.02 (0.98–1.06)
WHODAS Overall Score 0.005 (0.05) 0.01 0.93 1.00 (0.90–1.12)
DASS-21 Stress Score 0.15 (0.12) 1.63 0.20 1.17 (0.92–1.47)
_____________________
Abbreviations: BMI, body mass index; CSI, Central Sensitization Inventory; DASS, Depression Anxiety Stress Scales-21; HDI, The Henry Ford
Headache Disability Inventory; HDQ, Headache Disability Questionnaire; HIT-6, Headache Impact Test-6; WHODAS, World Health
Organization Disability Assessment Schedule 2.0
Bold numbers indicate statistical significance (p < 0.05)
237
CHAPTER SEVEN
Responsiveness of Disability Questionnaires
in Migraine and Non-Migraine Headaches
Chapter Seven has been submitted as:
Aguila ME, Leaver AM, Ng K, Rebbeck T. Responsiveness of disability questionnaires in
migraine and non-migraine headaches. Submitted to Quality of Life Research
238
As co-authors ofthe paper “Responsiveness of disability questionnaires in migraine and non-
migraine headache”, we confirm that Maria Eliza Ruiz Aguila has madethe following
contributions:
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Manuscript Title: Responsiveness of Disability Questionnaires in Migraine and Non-
Migraine Headaches
Authors: Maria-Eliza R. Aguila, MPhysio1,2, Andrew M. Leaver, PhD1, Karl Ng, PhD3,
Trudy Rebbeck, PhD1,4
Authors’ Institutional Information:

1
2
3
4
[email protected]
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Abstract
Purpose To examine the responsiveness of disability questionnaires for migraine and other
frequently presenting non-migraine headaches in primary care (tension-type headache and
cervicogenic headache).
Methods Data were collected from a longitudinal cohort study distinguishing migraine and
non-migraine headaches. Participants fulfilled the International Classification of Headache
Disorders-3 beta criteria for migraine, tension-type headache and/or cervicogenic headache.
Participants completed the Headache Impact Test-6, Headache Disability Inventory, Henry
Ford Headache Disability Inventory, Headache Disability Questionnaire, and the World
Health Organization Disability Assessment Schedule 2.0 at baseline and at 1, 3 and 6 months.
Participants also filled out a headache diary daily for 6 months. Internal responsiveness of the
questionnaires was evaluated by calculating effect size, and external responsiveness by
receiver operating characteristic curve analysis of change scores with headache frequency.
Results Headache Impact Test-6 and Headache Disability Questionnaire had the best internal
responsiveness for individuals with migraine and non-migraine. At short-term, effect sizes
(84% confidence intervals) ranged from 0.31 (0.07–0.56) to 0.47 (0.11–0.82). At medium-
term, effect sizes ranged from 0.40 (0.06–0.74) to 0.60 (0.26–0.94). Headache Disability
Questionnaire generally had the best external responsiveness to change in headache
frequency at both short- and medium-term [areas under the curve (95% confidence intervals)
0.52 (0.32–0.72) to 0.69 (0.49–0.89)].
Conclusions Headache Impact Test-6 and Headache Disability Questionnaire were the most
responsive disability questionnaires for individuals with migraine and non-migraine
headaches. These results add to the evidence on the usefulness of these measures in routine
assessment of outcomes in clinical practice.
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Keywords: migraine, tension-type headache, cervicogenic headache, disability, outcome
assessment
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Introduction
Headaches that most frequently present to primary care include migraine [1] and non-
migraine headaches such as tension-type headache [1] and cervicogenic headache [2]. These
headaches are associated with significant impact on the individuals [3, 4], who experience
disability when their headache and associated symptoms are active, as well as between
headache episodes. Disability must therefore be assessed in individuals with headaches
because it cannot be fully explained by headache frequency, intensity and symptoms [5].
Disability assessed using self-report questionnaires is among the outcomes recommended for
headache research [6–9]. A number of these questionnaires are specific to migraine and
assess disability during, but not between, migraine episodes [10]. Aside from migraine-
specific questionnaires, there are headache-specific questionnaires that are applicable across
different episodic or chronic headache types. These questionnaires include the Headache
Impact Test-6TM (HIT-6) [11], The Henry Ford Headache Disability Inventory (HDI) [12],
and the Headache Disability Questionnaire (HDQ) [13]. In addition to these headache-
specific questionnaires, generic disability questionnaires [e.g. 14, 15], including the World
Health Organization Disability Assessment Schedule 2.0 (WHODAS) [16], have also been
used. The above questionnaires differ in their constructs, reference time periods and scoring,
however all are reliable and valid measures of disability for individuals with headache [6, 10,
11, 14, 17]. To date, however, evidence is still lacking regarding which of these
questionnaires are most responsive, and therefore can be recommended to clinicians for their
ability to detect improvement or worsening of symptoms across migraine and non-migraine
headaches.
Responsiveness of self-report questionnaires is important to clinicians and patients
243
because it denotes ability to measure true change over time. Internal responsiveness describes
the ability of a measure to detect change over a particular time period [18], whilst external
responsiveness measures this change in relation to an external reference measure of health
status [18]. Thus far, only the responsiveness of the HIT-6 has been evaluated in specific
headache populations [11]. The HIT-6 has been shown to be responsive to self-reported
change in severity [19] and headache frequency and duration [20] in migraine and to self-
reported change and headache frequency in tension-type headache [21]. Other disability
questionnaires measuring slightly different constructs than HIT-6 (see Table 1) are available
for headache populations. The responsiveness of HDQ has been shown to be acceptable in a
general headache population who are seeking physiotherapy treatment [22] and the
responsiveness of WHODAS has been shown to be acceptable in a population with chronic
conditions, including migraine [23]. However, the responsiveness of these questionnaires has
not been compared across headache types nor compared with HIT-6. Comparing the
responsiveness of these questionnaires between migraine and non-migraine headache
populations could build on early evidence from our previous work indicating greater day-to-
day variability in disability in migraine compared to non-migraine headaches (forthcoming
publication). Investigating the responsiveness of HIT-6 compared with that of other disability
questionnaires in different headache types could reveal the ability of the questionnaires to
capture clinically meaningful changes and, therefore, the utility of these questionnaires as
outcome measures.
Therefore the primary aim of the study was to examine the responsiveness of
disability questionnaires for headache types presenting frequently in primary care, namely
migraine and non-migraine headaches. A secondary aim of the study was to explore whether
responsiveness of questionnaires differed between headache types.
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Methods
Participants and study design
Data were collected from a longitudinal cohort study distinguishing migraine and non-
migraine headaches. This research was granted ethics approval by the Human Research
Ethics Committee of The University of Sydney (Project Number 2014/536).
Recruitment of participants with recurrent headaches for the longitudinal cohort study
was done through advertisements posted at University, consumer support groups, community
bulletins, social media, and primary care and neurology clinics. Volunteers were eligible if
they were aged 18-65 years, had headaches for at least a year and had at least one headache
episode in the previous month.
Participants in the migraine group were those who were diagnosed as having migraine
by their attending neurologist/physician, whose headache features fulfilled the International
Classification of Headache Disorders (ICHD)-3 beta criteria for migraine [24] and in whom
other headache types were excluded as diagnosis. Participants in the non-migraine headache
group were those diagnosed as having tension-type or cervicogenic headache by a clinician
and whose headache features fulfilled the ICHD 3 beta criteria for tension-type headache or
cervicogenic headache.
Volunteers were excluded from either of the headache groups if their headaches were
due to any known secondary cause (other than cervicogenic) such as tumour, substance
withdrawal, surgery, etc. or if they had a pacemaker or fibrillator.
245
Procedures
All participants underwent initial telephone screening to confirm their eligibility. All eligible
participants completed self-administered questionnaires which covered information on
demographics and disability. Written informed consent was provided by all participants prior
to participation. Participants also provided baseline information on headache characteristics
including history, frequency of episodes, typical duration of each episode, and headache
intensity in the last month using the numerical rating scale (with anchors at 0 and 10: 0 = no
pain, 10 = worst pain possible). Participants then filled out an electronic diary administered
using the Research Electronic Data Capture (REDCap) application (Research Electronic Data
Capture, Nashville, Tennessee, USA) [25] hosted at The University of Sydney. Participants
recorded the presence of headaches daily for 6 months. Disability questionnaires were also
completed at baseline, 1 month, 3 months and 6 months.
Outcomes
Disability Disability was measured using the Headache Impact Test-6TM (HIT-6) [11], Henry
Ford Headache Disability Inventory (HDI) [12], Headache Disability Questionnaire [13], and
the 12-item version of the World Health Organization Disability Assessment Schedule 2.0
(WHODAS) [16]. The characteristics of these questionnaires are described in Table 1.
Headache frequency Frequency of headache episodes was counted from the number
of headache days reported in diary entries and summarized as number of headache episodes
per month. External responsiveness for headache frequency was calculated using 50%
reduction in headache frequency as the external criterion. This external criterion was selected
because it was among the recommended outcome measures in headache trials [6, 8, 9] and
246
was the primary indicator of recovery nominated as most important by patients [26, cited in
13]. This was used as the external criterion for external responsiveness. (See statistical
analysis.)
Statistical analyses
Demographic and baseline headache characteristics were summarized as mean and standard
deviation (SD) and frequency and percentage as appropriate. Additionally, questionnaire
scores at baseline, and at 1, 3 and 6 months were summarized as mean and SD.
Internal and external responsiveness were calculated for short-term and medium-term
changes for all questionnaire scores. Internal responsiveness was calculated using effect size
= mean change between baseline and follow-up scores (at 3 months for short-term and at 6
months for medium-term) divided by the standard deviation of the baseline score [27]. Effect
sizes of 0.2, 0.5 and 0.8 were interpreted as small, medium and large, respectively [18].
Statistical significance of effect size was established based on non-overlapping 84%
confidence intervals (CI), equivalent to Z test of means at the 0.05 level [28]. External
responsiveness was calculated using receiver operating characteristic (ROC) curve analysis.
ROC curves were plotted for each disability measure against the external criterion for short-
term change (from 1 month to 3 months) and medium term change (from 1 month to 6
months). The area under the curve (AUC) and 95% CI were then calculated to determine the
capacity of each questionnaire to discriminate between participants who improved on the
external criteria and those who did not. AUC values were interpreted as follows: ≥ 0.90 as
excellent; ≥ 0.80 and < 0.90 as good; ≥ 0.70 and < 0.80 as fair; and < 0.70 as poor [29]. ROC
curves between HIT-6 and the other disability questionnaires were compared using the
247
DeLong approach [30]. Data were excluded from analyses if any of the follow up
questionnaires was missing.
The calculated sample size for this study had 80% power to detect an effect size of
0.7, within the range of previously published responsiveness effect size of HIT-6 for chronic
migraine [20], at significance level of 0.05, whilst allowing for about 20% attrition. Statistical
analyses were conducted using Statistical Package for Social Sciences® statistical software,
version 24 (SPSS Inc., Chicago, Illinois, USA) for Windows and Microsoft Excel (Microsoft
Corporation, Redmond, Washington, USA; 2010), and Analyse-it for Microsoft Excel
(standard edition) (Analyse-it Software, Ltd, Leeds, England, UK; 2009).
Results
Participants
Eighty five eligible participants were included in the longitudinal study. Of these, 68
participants, 33 from the migraine group and 35 from the non-migraine group, had complete
baseline and follow-up questionnaires and therefore were included in analyses. Sixty
participants (88.2%) were female. Mean age (standard deviation, SD) was 37.74 (13.06)
years. Participants in the migraine group had longer history of headache, less frequent
episodes and more severe headache intensities than the non-migraine group (Table 2).
Questionnaire responses
Mean scores on all questionnaires at baseline and the three follow-up periods are shown in
Table 3. HIT-6 scores ranged from substantial to severe categories for the migraine group and
248
from moderate to substantial categories for the non-migraine group. None of the mean scores
were at the lowest 10% or highest 10% of the total score range for all the questionnaires.
Internal responsiveness
At short-term, internal responsiveness based on effect sizes (84% CI) was highest for HDQ
[0.37 (0.13–0.61)] and HIT-6 [0.31 (0.07–0.56)] for the total cohort (Table 4). Similarly,
HDQ and HIT-6 had the highest internal responsiveness for the migraine group [0.47 (0.11–
0.82) and 0.34 (-0.01–0.69), respectively] and for the non-migraine group [0.31 (-0.02–0.65)
and 0.32 (-0.02–0.66), respectively]. These effect sizes are interpreted as small. The overlap
in confidence intervals of effect sizes for HIT-6 and HDQ indicates no statistically significant
difference between these two questionnaires in short-term internal responsiveness.
At medium-term, internal responsiveness based on effect sizes (84% CI) was highest
for HIT-6 [0.52 (0.27–0.76) and HDQ [0.41 (0.16–0.65)] for the total cohort (Table 4).
Similarly, HIT-6 and HDQ had the highest internal responsiveness for the migraine group
[0.47 (0.12–0.83) and 0.46 (0.11–0.81), respectively] and for the non-migraine group [0.60
(0.26–0.94) and 0.40 (0.06–0.74), respectively]. These effect sizes are interpreted as small to
medium. The overlap in confidence intervals for HIT-6 and HDQ indicates no statistically
significant difference between these two questionnaires in medium-term internal
responsiveness based on effect sizes.
External responsiveness
At short-term, HDQ was the most responsive to change in headache frequency, considering
the total cohort, with AUC value (95% CI) of 0.61 (0.47–0.74) (Table 4). This AUC value is
249
interpreted as poor but better than chance probability of differentiating between participants
who improved and those who did not improve on headache frequency. For the migraine
group, HIT-6 was the most responsive disability questionnaire, with AUC value (95% CI) of
0.53 (0.29–0.77). This value is also interpreted as poor. For the non-migraine group, HDQ
was the most responsive, with AUC value (95% CI) of 0.69 (0.49–0.89), interpreted as fair.
At medium-term, HDQ was the most responsive to change in headache frequency for
the total cohort as well as the migraine and non-migraine groups. HDQ AUC values ranged
from 0.52–0.55, interpreted as poor in differentiating between participants who improved and
those who did not improve on headache frequency.
There were no significant differences for the AUC of the HIT-6 compared with the
other questionnaires for short-term and medium-term (P > 0.05) (Table 4). These results were
consistent for the whole cohort, for the migraine group, and for the non-migraine group.
Discussion
Results of this study indicate that HIT-6 and HDQ were the most responsive disability
questionnaires for individuals with migraine and non-migraine headaches with clinical
characteristics similar to the cohorts in this study. As expected, responsiveness was better for
headache-specific than generic questionnaires. Additionally, responsiveness was better at
medium-term than short-term. These results suggest that either HIT-6 or HDQ may be used
in assessing outcomes at 6 months in individuals with migraine and non-migraine headaches
undergoing their usual headache management.
The relative ranking of responsiveness for HIT-6 and HDQ differed for internal and
external responsiveness and between headache groups. However, these two questionnaires
consistently ranked first or second on any responsiveness calculation and headache group.
250
Additionally, there were no statistically significant differences in their responsiveness scores.
Collectively, these findings show that either HIT-6 or HDQ could be used in assessing
clinically important changes for migraine or non-migraine at 3 or 6 months.
Interestingly, HIT-6 showed the largest effect size for migraine and non-migraine
headaches at medium-term. These results support previous evidence on the responsiveness of
HIT-6 for people with recurrent headaches, in general [11], and for chronic migraine [20] and
tension-type headache in particular [21]. Results of this study also present new evidence on
the responsiveness of HDQ for both migraine and non-migraine headaches. The
comparatively high responsiveness of HDQ could be due to the scale options in the individual
items, allowing detection of small clinical changes. For example, one HDQ item asks “When
you have a headache while you work (or school), how much is your ability to work reduced?”
and presents options ranging from 0 (no reduction) to 10 (100% reduction) [13]. The HDQ
thus provides a greater range of options than the scales in the other disability questionnaires.
Further, HDQ had the best external responsiveness for the whole cohort, indicating that HDQ
related better than the other questionnaires with short-term and medium-changes in headache
frequency. This finding may reflect the fact that the HDQ includes items on frequency
(number of days) of specific headache symptoms and associated disability [13] while the
others do not.
The external responsiveness of the questionnaires was nearly no better than chance at
differentiating between those who improved on headache frequency and those who did not
after 3 or 6 months. These findings could be specific for individuals with clinical
characteristics similar to the cohorts in this study or could be due to the natural course of
these headaches in the absence of intervention in this study.
Results of external responsiveness may have also been different if other external
criteria were used. For example, higher external responsiveness scores for HDQ (ROC =
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0.76) were demonstrated in a general headache population when global change scores as
perceived by patients was used as the external criterion [22]. In another study, small to large
effect sizes were demonstrated for WHODAS in a population with chronic conditions when
improvement in severity of condition, categorized as mild, moderate or severe, was used as
the external criterion [23]. However we are confident that our choice of external criterion is
the most relevant to patients, as indicated by patients’ perception of its importance as an
outcome measure [26, cited in 13]. In addition, a reduction in headache frequency is among
the recommended external criteria based on guidelines for headache trials [6–9].
Findings of this study must therefore be considered whilst recognising a number of
methodological limitations. The heterogeneity of the non-migraine group restricts any
conclusion that can be drawn about the relative responsiveness of the questionnaires for
specific headache types. Whilst this study did not aim to compare responsiveness of
questionnaires between specific headache types, future studies could address such aim by
building on results of this present study. The sample size was relatively small and may not
have been adequate to detect effect sizes smaller than that hypothesised for this study. The
short observation period could have restricted the differences in responsiveness of
questionnaires between migraine and non-migraine groups. Therefore the responsiveness of
these questionnaires should be explored for longer-term changes in larger, homogenous
headache groups in controlled treatment efficacy trials.
Nevertheless, given the equal responsiveness of the HIT-6 and HDQ in migraine and
non-migraine headaches, clinicians could use either questionnaire, depending on the aspect of
disability of interest. For example, HDQ could be preferred when the goal is to measure the
percentage decrease in efficiency of tasks while HIT-6 may be preferred when the goal is to
measure the frequency of activity limitation.
252
Conclusions
In this study comparing responsiveness of disability questionnaires, HIT-6 and HDQ were the
most responsive to short-term and medium-term clinically relevant changes. These findings
are applicable to individuals with migraine and non-migraine headaches undergoing their
usual headache treatment. These findings add to the evidence on the usefulness of HIT-6 and
HDQ in routine assessment of outcomes in the clinics.
253
Acknowledgements We thank all the participants for their commitment to the study, and the
staff of the Sydney Specialist Physiotherapy Centre for their support during the conduct of
this study. We also thank the following for their help in recruiting participants: Headache
Australia, Australian Pain Society, Australian Pain Management Association, Painaustralia,
the editorial team of Ang Kalatas Australia, and Dr Craig Moore and the staff of Spinal
Solution.
Funding This research received no specific grant from any funding agency in the public,
commercial, or not-for-profit sectors.
Maria-Eliza Aguila was supported by a fellowship through the Doctoral Studies Fund
under the Expanded Modernization Program of the University of the Philippines. Trudy
Rebbeck was supported by a fellowship from the Australian National Health and Medical
Research Council (NHMRC).
Compliance with ethical standards
Conflicts of interest The authors declare no conflicts of interest.
Ethical approval All procedures performed in studies involving human participants were in
accordance with the ethical standards of the institutional and/or national research committee
and with the 1964 Helsinki Declaration and its later amendments or comparable ethical
standards.
Informed consent Informed consent was obtained from all individual participants included
in the study.
254
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Table 1. Characteristics of Headache Impact Test-6 [11], The Henry Ford Headache Disability Inventory [12], Headache Disability
Questionnaire [13], and World Health Organization Disability Assessment Schedule 2.0) [16]
Questionnaire Construct Reference Period Number of Number of Score Range Better State
Items Response Options Indicated By
Headache Impact Test-6 Impact of headache on work and When headache is 6 5 * Lower scores
36–78
(HIT-6) daily activities present or past 4
weeks
The Henry Ford Headache Emotional and functional Not specified 25 3 0–100 Lower scores
Disability Inventory disabilities due to headaches
(HDI)
Headache Disability Headache severity and effect of When headache is 9 11 0–90 Lower scores
Questionnaire (HDQ) headache on activity present or past month
World Health Functioning in the domains of Past 30 days 12 5 0–100 Lower scores
Organization Disability cognition, mobility, self-care,
Assessment Schedule 2.0 getting along, life activities, and
(WHODAS) participation
*
HIT-6 scores <49 indicate little or no effect (grade 1); scores of 50 to 55 indicate moderate effect (grade 2); scores of 56 to 59 indicate substantial effect (grade 3), and
scores ≥60 indicate severe effect (grade 4).
259
Table 2. Baseline characteristics of participants (n = 68)†
Migraine Non-Migraine
(n = 33) (n = 35)
Mean (SD) or n (%) Mean (SD) or n (%)
Age 39.91 (13.30) 35.69 (12.68)
Gender (female) 28 (84.8%) 32 (91.4%)
History of headache (years since first episode) 20.24 (12.51) 14.33 (14.90)
Frequency of headache in a month 4.89 (6.12) 9.31 (7.18)
Episode duration , minimum (hours) 15.12 (17.86) 12.58 (18.31)
Episode duration , maximum (hours) 64.73 (38.47) 95.13 (189.30)
Average headache intensity last month (0-10) ‡ 6.41 (1.74) 5.80 (1.57)
Taking medication for headache 30 (90.9%) 31 (81.6%)
Receiving physical therapy for headache 6 (18.2%) 10 (28.6%)
Receiving alternative treatment for headache 14 (42.4%) 15 (42.9%)
Abbreviation: SD, standard deviation

†
For continuous variables, values are presented as mean (SD); for categorical variables, values are presented as
frequency (%).
‡
Headache intensity: Numerical rating scale 0–10; 0 = no pain, 10 = worst possible pain
260
Table 3. Scores on self-report questionnaires at baseline and after 1, 3 and 6 months [mean (SD)]
Baseline After 1 Month After 3 Months After 6 Months
Migraine Non- Migraine Non- Migraine Non- Migraine Non-

Questionnaire Migraine Migraine Migraine Migraine
n = 33 n = 35 n = 33 n = 35 n = 33 n = 35 n = 33 n = 35
Headache Impact Test-6 (HIT-6) § 62.45 (5.81) 58.26 (6.55) 59.97 (6.56) 56.00 (8.14) 60.48 (5.42) 56.14 (8.35) 59.70 (8.21) 54.31 (9.30)
The Henry Ford Headache Disability Inventory (HDI) 37.45 (21.06) 28.57 (20.36) 36.36 (20.91) 29.60 (24.51) 38.36 (23.51) 27.60 (20.95) 37.58 (23.65) 28.57 (24.29)
Headache Disability Questionnaire (HDQ) 42.24 (16.41) 30.89 (15.73) 34.30 (16.96) 26.09 (17.36) 34.61 (17.42) 25.94 (16.07) 34.73 (18.29) 24.54 (16.49)
World Health Organization Disability Assessment Schedule 2.0 13.57 (13.95) 11.25 (10.38) 12.37 (14.70) 11.61 (11.17) 12.25 (14.15) 10.24 (9.55) 14.65 (16.84) 10.36 (10.60)
(WHODAS)
§
HIT-6 scores range from 36 to 78; scores <49 indicate little or no effect (grade 1); scores of 50 to 55 indicate moderate effect (grade 2); scores of 56 to 59 indicate substantial effect (grade 3),
and scores ≥60 indicate severe effect (grade 4).
Abbreviation: SD, standard deviation
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Table 4. Short-term and medium-term internal responsiveness of disability questionnaires
Questionnaires Effect Size (84% CI)

Short-Term Medium-Term
Total participants
Headache Impact Test-6 (HIT-6) 0.31 (0.07–0.56) 0.52 (0.27–0.76)
The Henry Ford Headache Disability Inventory (HDI) 0.003 (-0.24–0.24) -0.003 (-0.24–0.24)
Headache Disability Questionnaire (HDQ) 0.37 (0.13–0.61) 0.41 (0.16–0.65)
World Health Organization Disability Assessment Schedule 2.0 0.10 (-0.15–0.34) -0.01 (-0.25–0.24)
WHODAS)
Migraine Group
Headache Impact Test-6 (HIT-6) 0.34 (-0.01–0.69) 0.47 (0.12–0.83)
The Henry Ford Headache Disability Inventory (HDI) -0.04 (-0.39–0.30) -0.01 (-0.35–0.34)
Headache Disability Questionnaire (HDQ) 0.47 (0.11–0.82) 0.46 (0.11–0.81)
World Health Organization Disability Assessment Schedule 2.0 0.10 (-0.25–0.44) -0.08 (-0.42–0.27)
WHODAS)
Non-Migraine Group
Headache Impact Test-6 (HIT-6) 0.32 (-0.02–0.66) 0.60 (0.26–0.94)
The Henry Ford Headache Disability Inventory (HDI) 0.05 (-0.29–0.38) 0.00 (-0.34–0.34)
Headache Disability Questionnaire (HDQ) 0.31 (-0.02–0.65) 0.40 (0.06–0.74)
World Health Organization Disability Assessment Schedule 2.0 0.10 (-0.24–0.43) 0.08 (-0.25–0.42)
WHODAS)
Abbreviation: CI, confidence interval
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Table 5. Short-term and medium-term external responsiveness of disability questionnaires
Questionnaires Area Under the Curve DeLong Test Area Under the Curve DeLong Test
(95% CI) Statistic, P (95% CI) Statistic, P
Short-Term Medium-Term
Total participants
The Henry Ford Headache Disability Inventory (HDI) 0.38 (0.24–0.52) 0.42 0.38 (0.22–0.54) 0.52
Headache Disability Questionnaire (HDQ) 0.61 (0.47–0.74) 0.32 0.54 (0.40–0.69) 0.92
World Health Organization Disability Assessment 0.55 (0.41–0.68) 0.77 0.44 (0.28–0.60) 0.96
Schedule 2.0 WHODAS)
Migraine Group
Headache Disability Questionnaire (HDQ) 0.49( 0.30–0.68) 0.90 0.55 (0.32–0.77) 0.88
Non-Migraine Group
Headache Disability Questionnaire (HDQ) 0.69 (0.49–0.89) 0.12 0.52 (0.32–0.72) 0.62
Abbreviation: CI, confidence interval
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CHAPTER EIGHT
Conclusions
264
Conclusions
8.1 Overview of findings
The current standard in defining, classifying and diagnosing migraine and non-migraine
headaches involves differentiating each headache type based on headache characteristics
following the International Classification of Headache Disorders (ICHD) (1).The ICHD is
continuously being reviewed and revised according to evidence regarding pathophysiology
and characteristics of the headache type. Thus the application of ICHD, and therefore
classification and diagnosis of migraine and non-migraine headaches, may be augmented by a
better understanding of their pathophysiology and clinical characteristics. This thesis
verifiesthe ICHD as the standard for classifying headaches. It submits new evidence on the
potential of gamma-aminobutyric acid (GABA) as a biomarker for migraine and on the day-
to-day volatility and six-month clinical course of migraine and non-migraine headaches. This
thesis also presents additional data on clinical characteristics that differentiate migraine from
non-migraine headaches beyond the ICHD diagnostic criteria, such as impairments in
cervical muscle behaviour measured using the deep cervical extensor test and self-reported
disability measured using the Headache Disability Questionnaire or the Headache Impact
Test-6 as part of a combination of clinical characteristics differentiating migraine.
The aim of this thesis was to characterise migraine on the basis of its neurochemical profile
and clinical features not listed as diagnostic criteria in the ICHD, compared with non-
migraine headaches (TTH and CGH) that frequently present in primary care. Chapter Two
verified that ICHD is generally used to define patient populations of migraine and non-
migraine headaches in defined in clinical trials. Cutting-edge evidence is presented in
265
Chapters Three, Four and Six. First, GABA is a potential diagnostic biomarker for migraine,
given the higher concentration found in people with migraine compared with headache-free
controls (Chapter Three) and its association with pain and disability (Chapter Four). This is
the first time that the potential of GABA as a migraine biomarker is demonstrated, providing
direction for future research to investigate the pathophysiology of migraine, leading to
targeted management. Second, the day-to-day volatility of headache intensity and disability is
worse in migraine compared to non-migraine headaches as presented in Chapter Six. This is
the first time that the day-to-day volatility of migraine is depicted in detail, carrying
significance for addressing patients’ concern about the unpredictability of their headaches.
Evidence in addition to existing knowledge is presented in Chapter Five. Evidence is
presented suggesting that a combination of less pain on manual examination of the upper
cervical spine, less change in deep cervical extensors thickness during contraction, less
frequent headaches, and higher disability distinguished migraine from non-migraine
headaches. Chapter Six also showed that the disability changed in migraine and non-migraine
headaches, with a tendency to decline, over six months. This medium-term reduction in
disability was associated with the absence of painful cervical joint dysfunction. Chapter
Seven found that the best way to measure this change in disability over time could be using
the Headache Impact Test-6 (HIT-6) or the Headache Disability Questionnaire (HDQ). The
findings of this thesis addressgaps in the understanding of migraine, with implications
including expanding details in headache definitions, improving clinical practice, as well
asinforming future research. Ultimately, this thesis advances the search for effective
treatments and better health outcomes for people with migraine.
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8.2 Implications of the thesis
8.2.1. Implications for headache definitions
The evidence presented by this thesis provides impetus for the definitions of migraine and
non-migraine headache to be explained in more detail and broadened. The systematic review
in Chapter Two is the first study to provide an understanding of the characteristics of study
populations in treatment efficacy trials for migraine and non-migraine headaches. Whilst
89.5% of the trials reported adherence to the ICHD criteria in selecting the study populations,
details on the definition of study populations were unclear. First, 44.5% of the trials included
in the review did not report the method used to arrive at a headache diagnosis. Second, the
specific diagnostic criteria present among the study populations at baseline were generally
not provided. Such details are important, as they provide a clear description of study
populations, improving the transparency on the possible inclusion of people with overlapping
features or coexistent headache types. Such details could enable clinicians to decide on the
applicability of evidence to their patients (2), enhancing research translation. (3). Results of
this review therefore suggest that minimum standards for reporting characteristics of study
populations at baseline would be beneficial. Specifying the extent to which study populations
demonstrated ICHD diagnostic criteria at baseline should be among these minimum
standards. More detailed reporting of characteristics of study populations allow clarity of
headache populations in trials and ensure transparency and generalisabiltiy of evidence to
clinical practice(1, 4). This consideration of minimum standards could be a course of action
forguideline developers,who are involved in refining existing guidelines for clinical trials in
specific headache types (5-7).
267
The definition of migraine could be expanded by differentiating migraine as being associated
with more severe disability than non-migraine headaches. Whilst the ICHD presents migraine
as a more severe headache type than TTH based on headache intensity (1), the results of the
cross-sectional study demonstrated that migraine is more severe than non-migraine headaches
based on disability. Greater disability differentiates migraine from non-migraine headaches
when disability is considered in isolation or in combination with cervical musculoskeletal
impairments. Results of the cross-sectional cohort study also validate that cervical joint
dysfunction is less in migraine than in non-migraine headaches and present preliminary
evidence that cervical muscle behaviour is also impaired in migraine. Cervical
musculoskeletal impairments in migraine may be investigated further to determine their
utility in defining migraine. Nevertheless, the additional evidence presented in this thesis on
characteristics of migraine that may be useful in differential diagnosis therefore contributes to
the continued efforts of the headache community to clarify characteristics of headache types
to improve clinical practice and research.
8.2.2. Implications for clinical practice
The findings of Chapters Four, Five and Six have important implications in clinical practice
namely, headache assessment and differential diagnosis, prognosis and management. The
findings of this thesis show that the clinical characteristics that are relevant to assess and
consider in prognosis and management include cervical musculoskeletal impairments and
disability.
268
8.2.2.1. Assessment of cervical musculoskeletal impairments
Measuring cervical joint dysfunction will enable clinicians to characteriseand potentially
distinguish migraine from non-migraine headaches. The findings presented in Chapter Five
further validate that migraine has less upper cervical joint dysfunction than non-migraine
headaches as demonstrated by less frequent pain on manual provocation of the upper cervical
joints (p< 0.001) and less frequent positive flexion rotation test (p = 0.004). These findings
were consistent with previous reports of greater joint dysfunction in non-migraine headaches
compared to migraine (8-10). Taken together, clinicians can be confident that examination of
cervical joint dysfunction by palpation and the flexion rotation test should be retained to
assist with characterisation and differential diagnosis of migraine from non-migraine
headaches.
Cervical joint dysfunction was also one of the factors in a multifactorial model that explained
32.3 % of the variation in non-improvement in disability in the medium-term (p = 0.031)
(Chapter Six). Painful joint dysfunction was associated with 6 times higher odds of non-
improvement in disability [odds ratio (95% confidence interval) = 5.58 (1.14 to 27.42] (p =
0.040). Clinicians should therefore treatcervical dysfunction when present to potentially
improve the outcome in disability.
In contrast, measurement of cervical muscle impairment by clinicians to assist in differential
diagnosis of headaches was not supported by this thesis. However, its assessment may direct
management. We investigated a new test, the deep cervical extensor test (11), in Chapter Five
that measured muscle behaviour of deep cervical extensors during low-load contractions,
detected using real-time ultrasound imaging, We found no difference in muscle behaviour
269
between headache types when directly compared. However, there is some preliminary
evidence to explore this test further, given that this test contributed significantly (discriminant
function coefficient = 0.47) to a combination of measures distinguishing migraine from non-
migraine (Chapter Five). This test had not been evaluated in other cross-sectional studies to
date. Given the lack of difference demonstrated between headache groups, examination of the
behaviour of cervical extensors for the purposes of differential diagnosis cannot be
recommended at this point in time. However, as pointed out earlier, there is evidence that it
could be included amongst a battery of tests to characterise and possibly differentially
diagnose migraine.
Assessment of other domains of cervical muscle impairment such as muscle function, i.e.,
strength and endurance, to assist in the differentiation of migraine from non-migraine
headaches was also not supported by this thesis. However assessment of impairment to direct
treatment would be supported. Chapter Five found no difference in strength or endurance of
either cervical flexors or extensors between migraine and non-migraine headaches.
Unexpectedly, it was found that people with migraine also displayed these impairments
compared with controls. This supports the only other study that demonstrated reduced
strength in cervical muscles in episodic migraine compared to controls (12). Thus evidence
from this thesis indicates that impairments in cervical muscle function may also be present in
migraine. Considering this evidence, clinicians should assess cervical muscle function
impairment in migraine to identify possible targets for treatment.
Finally, clinicians are recommended to examine cervical musculoskeletal impairment in
combination with other clinical characteristics such as headache frequency and higher
disability scores. The findings of Chapter Five support that the combination of these tests
270
results in distinguishing migraine from non-migraine headaches with a sensitivity of 80% and
specificity of 75.6%. Clinicians now have additional evidence to consider when differentially
diagnosing, especially when the presenting case is ambiguous as to being pure migraine or a
non-migraine headache (Chapter Five).
a. Assessment of multidimensional pain and central sensitisation
symptoms
Implications of results of Chapter Four include measuring the multidimensional nature of
pain and central sensitisation symptoms to gain greater insight into the patient experience of
migraine as well as providing an association with the diagnosis and neurochemical
profile.These characteristics can be easily measured using self-report questionnaires such as
the Short-form McGill Pain Questionnaire-2 (SF-MPQ-2) (13) and the Central Sensitization
Inventory (CSI) (14), respectively. Responses to these questionnairesprovide rich information
on the sensory and emotional dimensions of the pain experience (13, 15) and underlying
pathophysiological mechanisms (14, 16). Consequently, clinicians are provided with a deeper
understanding of the patient’s headache experience, ultimately facilitating a more specific,
patient-centred approach to treatment.
In addition, both SF-MPQ-2 and CSI are useful in diagnosis and have an association with the
neurochemical profile of migraine. Individuals with CSI scores of ≥ 22.5 out of 100 are
nearly five times more likely to be indicative of migraine than no headache, with sensitivity
of 95% and specificity of 80% (Chapter Four). This cut-off score of 22.5 is lower than
previously published cut-off score of 40 for central sensitisation syndromes in general (17),
As such, this lower cut-off score means that migraine can be strongly suspected in individuals
271
with CSI scores of ≥ 22.5, improving the clinical utility of this index. Additionally, the fair
correlations of pain and central sensitisation scores with increased GABA levels in migraine
(Chapter Three) suggest that information from SF-MPQ-2 and CSI could be used to
understand the neurochemical profile of patients in the absence of spectroscopy data.
However, whether the association between multidimensional pain and central sensitisation
and brain GABA levels is specific for migraine, or true for any recurrent headache or chronic
pain condition,will be investigated in prospective research.
b. Assessment of disability
The findings of Chapters Five, Six and Seven support that clinicians should assess disability
for several reasons: to differentiate migraine, to predict the course of headache and to assess
outcome. Firstly, Chapter Five found that people with migraine had greater disability than
non-migraine. Disability is best assessed using the Headache Disability Questionnaire (HDQ)
(18), The Henry Ford Headache Disability Inventory (HDI) (19),or Headache Impact Test -6
(HIT-6) (20) because they showed good discriminative ability for migraine. For example,
scores on HDQ ≥ 27.5 out of 90 distinguish people with migraine from non-migraine
headaches, with sensitivity = 80.0%, specificity = 74.1%, and positive likelihood ratio = 3.09.
Similarly, total scores on HDI ≥19 out of 100 distinguish having migraine, with sensitivity =
80.0%, specificity = 67.1%, and positive likelihood ratio = 1.72. Scores on HIT-6, when
combined with results of musculoskeletalimpairment and headache frequency,also showed
good discriminative validity for migraine from non-migraine headaches (sensitivity = 80.0%,
specificity = 75.6%).
272
Further, clinicians should also assess disability because it may be associated with poor
prognosis and therefore could be targeted to potentially change the course of the headache.
The findings in Chapter Six demonstrated that higher disability at baseline was one factor in
a multifactorial model that explained 32.3 % of the variation in non-improvement in
disability in the medium-term (p = 0.031). Further, the results presented in Chapter Six
showed that disability changed over the medium-term in migraine and non-migraine
headaches. Given this, assessment of disability at baseline may assist clinicians with
understanding the prognosis and course of headache.
Finally the findings of Chapter Seven support the use of disability questionnaires by
clinicians to measure outcome. Clinically relevant changes in disability may be measured
using the HIT-6 or HDQ, with acceptable responsiveness [effect sizes (95% confidence
interval) ranging from 0.40 (0.06 to 0.74) to 0.69 (0.49 to 0.89)].Chapter Seven thus builds on
the evidence presented in Chapter Five on the usefulness of HIT-6 and HDQ, not only to
characterise disability in migraine and non-migraine headaches,but also to measure clinically
relevant change over time in migraine (21, 22) and non-migraine headaches (23).
c. Implications for patient education
Overall, the results of this thesis have implications for patient education with regard to
diagnosis, prognosis and management. As a result of findings of Chapters Three, Four and
Five, clinicians can have greater confidence to differentiate migraine on the basis of clinical
and characteristics, including disability profile, and can communicate this to their patients.
Clinicians will be able to educate patients with migraine about the nature of their headaches
with greater clarity. The factors associated with non-improvement in disability and the high
273
day-to-day volatility especially of migraine headaches presented in Chapter Six could be
included in patient education strategies. Previous work has established the critical role of
patient education in effective multidisciplinary headache management. Educating patients
about the characteristics of their headaches enhances self-efficacy, motivation and treatment
adherence, eventually resulting in improved outcomes (24-26). In particular, providing
patients with information on the behaviour of headaches addresses their frustration because of
the unpredictability of their headaches (27, 28) and potentially helps them align their
expectations accordingly. Finally, the work in Chapters Five and Six demonstrated that
cervical musculoskeletal impairments are present in 10% of participants with migraine..
Explaining to patients that these impairments could be targeted when present, potentially
reducing disability (Chapter Six), may provide patients with some hope.
8.2.3. Limitations of the thesis
The findings of this thesis must be interpreted with caution in light of a number of
methodological limitations of the studies. One limitation of this thesis is that the spectroscopy
technique employed in Chapters Three and Fourmight not provide a complete profile of brain
neurochemicals in migraine. Although MEGA-PRESS is considered to be the best available
technique for separating and quantifying GABA, it is possible that even this best
spectroscopy technique might not have achieved complete separation of GABA from
macromolecules. Future advances in spectroscopy might allow more complete separation,
and therefore more accurate measurement of GABA. As regards distinguishing migraine
from non-migraine headaches, an important caveat in considering the findings presented in
Chapters Five through Seven is that the heterogeneity of the non-migraine group prevents any
274
conclusion to be drawn about cervical musculoskeletal impairments and clinical course
specifically for CGH or TTH. Prospective studies with pure headache groups that have larger
sample sizes would be better suited to distinguish specific headache types. Larger sample
sizes of prospective population- or clinic-based research could also allow for a more in-depth
investigation of numerous possible predictors of non-improvement in headaches. Such
research could build on findings of our exploratory longitudinal cohort study presented in
Chapter Six. There is also reason for cautious interpretation of results related to self-report
questionnaires in Chapters Four through Seven due to possible test order effects. Although
the consistent presentation of questionnaires across participants eliminated one possible
confounding variable, we did not test any effect the order of administration of questionnaires
may have on the responses of the participants. Lastly, the lack of follow up measurements of
cervical musculoskeletal impairments and the limited observation period in the study
presented in Chapter Six do not allow any conclusion on long-term clinical courses of
headaches and possible association of any change in cervical musculoskeletal impairments.
These limitations may be addressed in future research.
8.2.4. Directions for future research
Evidence presented in this thesis has implications for future research to further elucidate the
nature of migraine toward enhancing treatment. These include validating GABA as a
biomarker for migraine, specifying cervical musculoskeletal impairments in headaches, and
further characterising the clinical course and prognosis of migraine and non-migraine
headaches.
275
8.2.4.1 Validating GABA as a biomarker for migraine
The breakthrough presented in Chapters Three and Four regarding the potential of GABAas a
biomarker for migraine may be explored further in future studies. Validating GABA as a
migraine biomarker would address the lack of established biomarkers (29, 30)and would
consequently allow refinement of headache definitions to be based on more objective markers
than headache features. In the process of validating GABA as a biomarker for migraine, its
role in migraine pathophysiology may be investigated.
The first step toward validating GABA as a biomarker is to examine the association of brain
GABA levels with other clinical characteristics of migraine (31). Such characteristics should
include those related to the headache (such as triggers, aura, associated symptoms during the
headache phase, e.g. nausea and photophobia, and symptoms during the postdrome phase).
Also it may be worth exploring the associations of brain GABA levels with personal factors,
including multidimensional pain, central sensitisation, emotional state and lifestyle habits
(32, 33), and other known risk factors for migraine progression [such as obesity (34), genetic
predisposition and medication overuse (32)]. Whilst multidimensional pain and central
sensitisation were found to be associated with brain GABA levels in this thesis (Chapter
Four), these findings need to be cross-validated in future cross sectional studies with larger
sample sizes.
The second step in establishing GABA as a biomarker is to determine that increased
concentration of GABA in the brain is unique to migraine. Hence concentration of GABA
should be compared between different headache types, chronic pain conditions and pain-free
controls in a larger cross sectional studies. This would elucidate whether the increase in
276
GABA concentrations in migraine is specific for migraine, to headaches in general or to any
chronic pain condition.
A longitudinal study would enable identification of causal relationships between GABA
levels and the onset and phases of migraine, and any change in clinical characteristics such as
pain and disability. Identifying these causal relationships would clarify the pathophysiology
of migraine and the mechanisms causing the increased GABA levels. Next, to identify the
GABA-related mechanisms, preclinical studies using animal models may help inform the
design of randomised controlled trials targeting reduction in GABA levels. Ultimately curing
migraine with an intervention (e.g. pharmaceutical agent) aimed at the potential cause
(increased GABA levels would confirm the role of GABA in migraine pathophysiology.
Proving the efficacy of the intervention targeting GABA would then complete the validation
of GABA as a migraine biomarker.
8.2.4.2 Specifying cervical musculoskeletal impairments in headaches
Cervical musculoskeletal impairments in migraine compared to non-migraine headaches
demonstrated in Chapter Five need to be exploredfurther. First, larger cross-sectional cohort
studies with pure groups for migraine, TTH and CGH would enable differentiation between
specific headache types. Second, the discriminative validity of the combination of tests to
differentiate migraine from non-migraine headaches should be evaluated in future cohort
studies. To accomplish this, headache classification using the combination of manual
examination of the upper cervical spine, real-time ultrasound measurement of the change in
deep cervical extensors thickness during low-load contraction, frequency of headaches, and
disability may be compared with classification using the ICHD. Such studies would hopefully
277
resolve the conflicting findings regarding the presence of these cervical musculoskeletal
impairments in migraine.
8.2.4.3 Characterising the clinical course and prognosis of migraine and non-
migraine headaches better
Lastly, the clinical course and prognosis of migraine and non-migraine headaches may be
studied further to build on findings of Chapters Six and Seven. This may be achieved through
a longitudinal clinical trial over at least one year, preferably longer to consider the volatility
of headache symptoms demonstrated in the medium-term in Chapter Six. Such longitudinal
clinical trial study should entail at least one intervention and prospective measurements of
headache characteristics and other putative predictors repeated over time. Additional studies
on clinical course would address the scarcity of evidence in this area and may eventually
open avenues for specific management of headaches.
The recommendations presented in this chapter for guideline expansion, clinical practice and
research are envisioned to inform the design of targeted and effective treatment for migraine
and for headaches in general. Whilst much is still left to be known about headaches, every
effort to increase the understanding of the nature of headaches contributes toward improved
definitions of headaches. Correct headache classification is a necessary step toward
development of effective treatments. The application of findings presented in this thesis will
therefore contribute to better health outcomes for patients and, ultimately, to the reduction of
the global burden of headaches.
278
For Meg, this is, pardon the pun, MIND-BLOWING
news!…Meg now awaits studies that will solve
exactly how GABA links with migraine: Does GABA
start her migraine attack? Does GABA stop it? Much
more remains unknown, but each piece to the
migraine puzzle raises hope for its cure.

Illustration by David Val Christian B. Agoncillo, 2014
for presentations related to studies in this thesis
[Excerpt from Three-Minute Thesis Presentation (3MT®) by Maria Eliza Ruiz Aguila;
Winner, Faculty of Health Sciences 3MT® 2014]
279
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APPENDICES
284
List of appendices
APPENDIX 1 Supplemental materials for systematic review (Chapter Two)............... 289
Search Strategy: MEDLINE OVID.............................................................................. 290
Data extraction form.................................................................................................... 291
Reference list for studies included in the review .......................................................... 293
APPENDIX 2 Ethics approvals for studies presented in this thesis (Chapters Three
through Seven) ................................................................................................................ 323
Letters of approval from The University of Sydney Human Research Ethics Committee
for studies evaluating GABA levels in migraine (Chapters Three and Four) ................ 324
Letters of approval from The University of Sydney Human Research Ethics Committee
for studies differentiating migraine from non-migraine headaches (Chapters Five through
Seven) ......................................................................................................................... 328
APPENDIX 3 Levels of excitatory and other brain chemicals in migraine detected using
proton magnetic resonance spectroscopy (Supplement to Chapter Three) .................. 332
Introduction ................................................................................................................. 333
Magnetic resonance spectroscopy data acquisition....................................................... 334
Results ........................................................................................................................ 337
Conclusions ................................................................................................................. 340
References ................................................................................................................... 341
285
APPENDIX 4 Protocol for cross-sectional study on GABA levels in migraine (Chapters
Three and Four) .............................................................................................................. 343
Project sequence .......................................................................................................... 345
Participant forms and questionnaires ........................................................................... 351
Participant information statement and consent form ............................................... 351
Demographic details .............................................................................................. 356
Pain questionnaires ................................................................................................ 359
Short-form McGill Pain Questionnaire-2 .................................................... 359
Central Sensitization Inventory .................................................................. 360
Depression Anxiety Stress Scale-21 ....................................................................... 361
Disability questionnaires
Headache Disability Questionnaire............................................................. 362
Headache Impact Test-6 ............................................................................. 363
The Henry Ford Headache Disability Index ............................................... 364
APPENDIX 5 Protocol for cross-sectional and longitudinal studies on differentiating
migraine and non-migraine headaches (Chapters Five through Seven) ....................... 371
Project sequence .......................................................................................................... 374
Participant questionnaires ............................................................................................ 380
Participant information statement and consent form ............................................... 380
Baseline questions ................................................................................................. 384
Pain questionnaires ................................................................................................ 388
Short-form McGill Pain Questionnaire-2 .................................................... 388
Central Sensitization Inventory .................................................................. 390
286
Disability questionnaires ........................................................................................ 391
Headache Impact Test-6 ............................................................................. 391
The Henry Ford Headache Disability Index ............................................... 392
Headache Disability Questionnaire............................................................. 393
WHO Disability Assessment Schedule 2.0 ................................................. 395
Health questionnaires ............................................................................................ 396
The Self-Administered Comorbidity Questionnaire .................................... 396
Depression Anxiety Stress Scale-21 ........................................................... 397
Pittsburgh Sleep Quality Index .................................................................. 398
International Physical Activity Questionnaire ............................................. 402
Clinical examination .............................................................................................. 411
APPENDIX 6 Media coverage for cross-sectional study on GABA levels in migraine
(Chapter Three) .............................................................................................................. 446
Media report ................................................................................................................ 447
APPENDIX 7 Cover art published in Journal of Pain (Chapter Four) ......................... 458
Journal cover ............................................................................................................... 459
APPENDIX 8 The clinical significance of immediate symptom responses to manual
therapy treatment for neck pain: Observational secondary data analysis of a
randomized trial .............................................................................................................. 461
Abstract ....................................................................................................................... 464
Introduction ................................................................................................................. 466
287
Methods ...................................................................................................................... 469
Results ........................................................................................................................ 473
Discussion ................................................................................................................... 476
Conclusions ................................................................................................................. 480
References ................................................................................................................... 481
Tables ......................................................................................................................... 483
Figure .......................................................................................................................... 485
288
APPENDIX 1
Supplemental Materials for Chapter Two:
Definitions and Participant Characteristics of Frequent
Recurrent Headache Types in Clinical Trials:
A Systematic Review
Appendix 1is the peer reviewed version of supplemental materials to the following article:
Aguila ME, Rebbeck T, Mendoza KG, De La Peña MG, Leaver AM. Definitions and
participant characteristics of frequent recurrent headache types in clinical trials: A systematic
review. Cephalalgia.Epub2017 Apr 25. doi: 10.1177/0333102417706974, which has been
published in online form ahead of print at
http://journals.sagepub.com/doi/suppl/10.1177/0333102417706974
289
Appendix A
Search Strategy: MEDLINE OVID
Definitions and participant characteristics of frequent recurrent headache types in clinical
studies: A systematic review
1 exp Headache/
2 exp Cluster Headache/
3 exp Tension-Type Headache/
4 exp Migraine Disorders/
5 exp Post-Traumatic Headache/
6 cervicogenic headache.mp.
7 exp Headache Disorders, Primary/
8 exp Headache Disorders/
9 primary headache.mp.
10 (headache* or cephalagi* or migrain*).mp
11 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10
12 exp Clinical Trial/
13 (clin* adj25 trial*).ti,ab.
14 ((singl* or doubl* or trebl* or tripl*) adj25 blind*).mp. or mask*.ti,ab.
15 ((singl* or doubl* or trebl* or tripl*) adj25 (blind* or mask*)).ti,ab.
16 exp Placebos/
17 placebo*.ti,ab.
18 random*.ti,ab.
19 exp Cross-Over Studies/
20 exp Double-Blind Method/
21 double-blind procedure*.mp.
22 exp Randomized Controlled Trial/
23 exp Single-Blind Method/
24 Single-Blind Procedure*.mp.
25 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24
26 11 and 25
27 limit 26 to (English language and yr="2005 -Current")
28 limit 27 to humans
290
Appendix B
Data extraction form
Definition of study population in headache studies based on selection and diagnosis of participants
and ICHD headache features at baseline
B.1 Migraine studies
Study by Participant selection and diagnosis ICHD diagnostic criteria reported as baseline characteristics
first author,
year Method Diagnostic Inclusion Exclusion criteria Headache Unilateral Pulsating Moderate or Aggravation Nausea Photophobia
of classificati criteria other attacks location quality severe pain by or and/or and
diagnosis on used than diagnostic lasting 4-72 intensity causing vomiting phonophobi
criteria hours avoidance a
(untreated of routine
or physical
unsuccessfu activity
lly treated)
B.2 Tension-type headache studies
first
author, Method of Diagnostic Inclusion Exclusion Headache Bilateral Pressing/ti Mild or Not No nausea No more Headache
year diagnosis classification criteria criteria lasting location ghtening moderate aggravated or than one of occurring
used other than from 30 (non- intensity by routine vomiting photophob on ≥15
diagnostic minutes to pulsating) physical ia or days/mont
criteria 7 days quality activity phonophob h on
ia average
for >3
months
(≥180
days/year)
291
B.3 Cluster headache studies
first
author, Method of Diagnostic Inclusion criteria Exclusion Severe or Ipsilateral Ipsilateral Ipsilateral Ipsilateral Ipsilateral A sense of Attacks
year diagnosis classificati other than criteria very severe conjunctiv nasal eyelid forehead miosis restlessnes have a
(Appendix on used diagnostic unilateral al injection congestion oedema and facial and/or s or frequency
B criteria orbital, and/or and/or sweating ptosis agitation from one
reference) supraorbita lacrimation rhinorrhoe every other
l and/or a day to 8
temporal per day
pain
lasting 15-
180
minutes if
untreated
B.4 Cervicogenic headache studies
Study by first Participant selection and diagnosis ICHD diagnostic criteria reported as baseline characteristics
author, year
Method of Diagnostic Inclusion criteria Exclusion criteria Pain from neck Related diagnostic Abolition of Pain resolution
diagnosis classification other than and perceived in evidence headache after treatment
used diagnostic criteria head and/or face following
blockade
292
Appendix C
Reference List for Studies Included in the Review
Migraine studies
1. Alemdar M, Pekdemir M, Selekler HM. Single-dose intravenous tramadol for acute
migraine pain in adults: A single-blind, prospective, randomized, placebo-controlled
clinical trial. Clin Ther 2007; 29: 1441–7.
2. Allais G, Bussone G, D'Andrea G, et al. Almotriptan 12.5 mg in menstrually related
migraine: A randomized, double-blind, placebo-controlled study. Cephalalgia 2011;
31: 144–51.
3. Allais G, Romoli M, Rolando S, et al. Ear acupuncture in the treatment of migraine
attacks: A randomized trial on the efficacy of appropriate versus inappropriate
acupoints. Neurol Sci 2011; 32: S173–5.
4. Almén-Christensson A, Hammar M, Lindh-Åstrand L, et al. Prevention of menstrual
migraine with perimenstrual transdermal 17-β-estradiol: A randomized, placebo-
controlled, double-blind crossover study. Fertil Steril 2011; 96: 498–500.e1
5. Alstadhaug KB, Odeh F, Salvesen R, et al. Prophylaxis of migraine with melatonin: A
randomized controlled trial. Neurology 2010; 75: 1527–32.
6. Anand KS, Prasad A, Singh MM, et al. Botulinum toxin type a in prophylactic
treatment of migraine. Am J Ther 2006; 13: 183–7.
7. Antal A, Kriener N, Lang N, et al. Cathodal transcranial direct current stimulation of
the visual cortex in the prophylactic treatment of migraine. Cephalalgia 2011; 31:
820–8.
293
8. Asadollahi S, Heidari K, Vafaee R, et al. Promethazine plus sumatriptan in the
treatment of migraine: A randomized clinical trial. Headache 2014; 54: 94–108.
9. Aurora SK, Dodick DW, Turkel CC, et al. Onabotulinumtoxina for treatment of
chronic migraine: Results from the double-blind, randomized, placebo-controlled
phase of the PREEMPT 1 trial. Cephalalgia 2010; 30:793–803.
10. Aurora SK, Gawel M, Brandes JL, et al. Botulinum toxin type a prophylactic
treatment of episodic migraine: A randomized, double-blind, placebo-controlled
exploratory study. Headache 2007; 47: 486–99.
11. Aurora SK, Rozen TD, Kori SH, et al. A randomized, double blind, placebo-
controlled study of map0004 in adult patients with migraine. Headache 2009; 49:
826–37.
12. Aurora SK, Silberstein SD, Kori SH, et al. Map0004, orally inhaled dhe: A
randomized, controlled study in the acute treatment of migraine. Headache 2011; 51:
507–17.
13. Barbanti P, Fofi L, Dall'Armi V, et al. Rizatriptan in migraineurs with unilateral
cranial autonomic symptoms: A double-blind trial. J Headache Pain 2012; 13: 407–
14.
14. Blumenfeld AM, Schim JD, Chippendale TJ. Botulinum toxin type a and divalproex
sodium for prophylactic treatment of episodic or chronic migraine. Headache 2008;
48: 210–20.
15. Borhani Haghighi A, Motazedian S, Rezaii R, et al. Cutaneous application of menthol
10% solution as an abortive treatment of migraine without aura: A randomised,
294
double-blind, placebo-controlled, crossed-over study. Int J Clin Pract 2010; 64: 451–
6.
16. Brandes J, Poole A, Kallela M, et al. Short-term frovatriptan for the prevention of
difficult-to-treat menstrual migraine attacks. Cephalalgia 2009; 29: 1133–48.
17. Brandes JL, Kudrow D, Cady R, et al. Eletriptan in the early treatment of acute
migraine: Influence of pain intensity and time of dosing. Cephalalgia 2005; 25: 735–
42.
18. Brandes JL, Kudrow D, Stark SR, et al. Sumatriptan-naproxen for acute treatment of
migraine: A randomized trial. JAMA 2007; 297: 1443–54.
19. Brandes JL, Kudrow DB, Rothrock JF, et al. Assessing the ability of topiramate to
improve the daily activities of patients with migraine. Mayo Clin Proc 2006; 81:
1311–9.
20. Bromberg J, Wood ME, Black RA, et al. A randomized trial of a web-based
intervention to improve migraine self-management and coping. Headache 2012; 52:
244–61.
21. Cady R, Martin V, Mauskop A, et al. Efficacy of rizatriptan 10 mg administered early
in a migraine attack. Headache 2006; 46: 914–24.
22. Cady R, Saper J, Dexter K, et al. A double-blind, placebo-controlled study of
repetitive transnasal sphenopalatine ganglion blockade with Tx360® as acute
treatment for chronic migraine. Headache 2015; 55:101–16.
23. Cady RK, Goldstein J, Nett R, et al. A double-blind placebo-controlled pilot study of
sublingual feverfew and ginger (LipiGesic™M) in the treatment of migraine.
Headache 2011; 51: 1078–86.
295
24. Cady RK, Martin VT, Geraud G, et al. Rizatriptan 10-mg odt for early treatment of
migraine and impact of migraine education on treatment response. Headache 2009;
49: 687–96.
25. Cady RK, Mathew N, Diener HC, et al. Evaluation of carisbamate for the treatment of
migraine in a randomized, double-blind trial. Headache 2009; 49: 216–26.
26. Cady RK, McAllister PJ, Spierings ELH, et al. A randomized, double-blind, placebo-
controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825)
in the treatment of acute migraine (The TARGET study). Headache 2015; 55: 88–
100.
27. Cady RK, Saper J, Dexter K, et al. Long-term efficacy of a double-blind, placebo-
controlled, randomized study for repetitive sphenopalatine blockade with bupivacaine
vs saline with the Tx360® device for treatment of chronic migraine. Headache 2015;
55: 529–42.
28. Cerritelli F, Ginevri L, Messi G, et al. Clinical effectiveness of osteopathic treatment
in chronic migraine: 3-armed randomized controlled trial. Complement Ther Med
2015; 23: 149–56.
29. Cete Y, Dora B, Ertan C, et al. A randomized prospective placebo-controlled study of
intravenous magnesium sulphate vs. metoclopramide in the management of acute
migraine attacks in the emergency department. Cephalalgia 2005; 25: 199–204.
30. Chabi A, Zhang Y, Jackson S, et al. Randomized controlled trial of the orexin
receptor antagonist filorexant for migraine prophylaxis. Cephalalgia 2015; 35: 379–
88.
296
31. Chambers JB, Seed PT, Ridsdale L. Clopidogrel as prophylactic treatment for
migraine: A pilot randomised, controlled study. Cephalalgia 2014; 34: 1163–8.
32. Chankrachang S, Arayawichanont A, Poungvarin N, et al. Prophylactic botulinum
type A toxin complex (Dysport) for migraine without aura. Headache 2011; 51: 52–
63.
33. Coffee AL, Sulak PJ, Hill AJ, et al. Extended cycle combined oral contraceptives and
prophylactic frovatriptan during the hormone-free interval in women with menstrual-
related migraines. J Womens Health (Larchmt) 2014; 23: 310–7.
34. Conforto AB, Amaro E, Jr., Goncalves AL, et al. Randomized, proof-of-principle
clinical trial of active transcranial magnetic stimulation in chronic migraine.
Cephalalgia 2014; 34: 464–72.
35. Connor KM, Shapiro RE, Diener HC, et al. Randomized, controlled trial of
telcagepant for the acute treatment of migraine. Neurology 2009; 73: 970–7.
36. Dahlof CG, Hauge AW, Olesen J. Efficacy and safety of tonabersat, a gap-junction
modulator, in the acute treatment of migraine: A double-blind, parallel-group,
randomized study. Cephalalgia 2009; 29: 7–16.
37. DaSilva AF, Mendonca ME, Zaghi S, et al. tDCS-induced analgesia and electrical
fields in pain-related neural networks in chronic migraine Headache 2012 ; 52:1283–
1295.
38. Diener HC, Barbanti P, Dahlöf C, et al. BI 44370 TA, an oral CGRP antagonist for
the treatment of acute migraine attacks: Results from a phase II study. Cephalalgia
2011; 31: 573–84.
297
39. Diener HC, Bussone G, Van Oene JC, et al. Topiramate reduces headache days in
chronic migraine: A randomized, double-blind, placebo-controlled study. Cephalalgia
2007; 27: 814–23.
40. Diener HC, Dodick DW, Aurora SK, et al. Onabotulinumtoxina for treatment of
chronic migraine: Results from the double-blind, randomized, placebo-controlled
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203. Hirata K, Tatsumoto M, Araki N, et al. Multi-center randomized control trial of
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204. Holroyd KA, Labus JS, Carlson B. Moderation and mediation in the psychological
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207. Karadas O, Inan LE, Ulas U, et al. Efficacy of local lidocaine application on anxiety
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208. Lindelof K, Bendtsen L. Memantine for prophylaxis of chronic tension-type headache
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209. Medvedeva LA, Gnezdilov AV, Zagorul'ko OI, et al. Efficacy of neuroprotectors in
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210. Melchart D, Streng A, Hoppe A, et al. Acupuncture in patients with tension-type
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211. Packman E, Packman B, Thurston H, et al. Lumiracoxib is effective in the treatment
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212. Silberstein SD, Gobel H, Jensen R, et al. Botulinum toxin type A in the prophylactic
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213. Soderberg E, Carlsson J, Stener-Victorin E. Chronic tension-type headache treated
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219. Cittadini E, May A, Straube A, et al. Effectiveness of intranasal zolmitriptan in acute
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A double blind study. Can J Neurol Sci 2014; 41: 603–10.
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321
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322
APPENDIX 2
Ethics Approvals
Appendix 2 presents ethics approvals from The University of Sydney Human Research Ethics
Committee for studies presented in Chapters Three through Seven.
323
RESEARCH INTEGRITY
Human Research Ethics Committee
Web: http://sydney.edu.au/ethics/
Email: [email protected]
Address for all correspondence:

Level 6, Jane Foss Russell Building - G02
NSW 2006 AUSTRALIA
Ref: [SA/KFG]
31 October 2012
Prof Kathryn Refshauge

Dean, Faculty of Health Sciences
Dear Professor Refshauge
Thank you for your correspondence dated 17 August 2012 (received 25 October 2012), addressing
comments made to you by the Human Research Ethics Committee (HREC).
On 30 October 2012 the Chair of the HREC considered this information and approved your protocol
entitled “Development of "neurochemical signatures" as a novel diagnostic technique for
headache.”
Details of the approval are as follows:
Protocol No.: 15048
Approval Date: 30 October 2012
First Annual Report Due: 31 October 2013
Authorised Personnel: Prof Kathryn Refshauge

A/Prof Jim Lagopoulos
Prof Patrick Brennan
Dr Markus Huebscher
Dr Andrew Leaver
Dr Trudy Rebbeck
Documents Approved:
Document Version Number Date

nd
Recruitment Advertisement Version 2 22 October 2012
nd
Participant Information Statement Version 2 22 October 2012
rd
Participant Consent Form Version 1 23 December 2011
th
Letter to neurologists Version 2 18 August 2012
Standardised Measures: Headache Disability Index, n/a n/a
Short-Form McGill Pain Questionnaire,
HREC approval is valid for four (4) years from the approval date stated in this letter and is granted
pending the following conditions being met:
Manager Human Ethics Human Ethics Secretariat: 324

ABN 15 211 513 464
CRICOS 00026A
Dr Margaret Faedo Ms Karen Greer T: +61 2 8627 8171 E: [email protected]
T: +61 2 8627 8176 Ms Patricia Engelmann T: +61 2 8627 8172 E: [email protected]
E: margaret.faedo @sydney.edu.au Ms Kala Retnam T: +61 2 8627 8173 E: [email protected]
Condition/s of Approval
 Continuing compliance with the National Statement on Ethical Conduct in Research Involving
Humans.
 Provision of an annual report on this research to the Human Research Ethics Committee from
the approval date and at the completion of the study. Failure to submit reports will result in
withdrawal of ethics approval for the project.
 All serious and unexpected adverse events should be reported to the HREC within 72 hours.
 All unforeseen events that might affect continued ethical acceptability of the project should be
reported to the HREC as soon as possible.
 Any changes to the protocol including changes to research personnel must be approved by
the HREC by submitting a Modification Form before the research project can proceed.
Chief Investigator / Supervisor’s responsibilities:
1. You must retain copies of all signed Consent Forms (if applicable) and provide these to the HREC
on request.
2. It is your responsibility to provide a copy of this letter to any internal/external granting agencies if
requested.
Please do not hesitate to contact Research Integrity (Human Ethics) should you require further
information or clarification.
Yours sincerely
Dr Stephen Assinder
Chair
This HREC is constituted and operates in accordance with the National Health and Medical
Research Council’s (NHMRC) National Statement on Ethical Conduct in Human Research
(2007), NHMRC and Universities Australia Australian Code for the Responsible Conduct of
Research (2007) and the CPMP/ICH Note for Guidance on Good Clinical Practice.
325
Page 2 of 2
2012/581 - Change in Personnel Outcome Page 1 of 1
2012/581 - Change in Personnel Outcome

Human Ethics [[email protected]]
Sent: Monday, 27 May 2013 11:30 AM
To: Kathryn Refshauge [[email protected]]
Cc: Maria Eliza Aguila; Andrew Leaver [[email protected]]; [email protected]; Trudy Rebbeck
[[email protected]]; Patrick Brennan [[email protected]]; Jim Lagopoulos
[[email protected]]
Dear Professor Refshauge
Project Title: Development of "neurochemical signatures" as a novel diagnostic

technique for headache.
Project No: 2012/581
Thank you for submitting a Change in Personnel form for the above project. Your
request was considered by Research Integrity (Human Ethics).
The change has been approved.
All current investigators: Refshauge Kathryn; Aguila Maria; Leaver Andrew; Heubscher
Marcus; Rebbeck Trudy; Brennan Patrick; Lagopoulos Jim;
Please do not hesitate to contact Research Integrity (Human Ethics) should you
require further information or clarification.
Regards,
Human Ethics Administration
326
https://bn1prd0111.outlook.com/owa/?ae=Item&t=IPM.Note&id=RgAAAACIZD1mAm... 23-Aug-13
Research Integrity
Human R
Research Ethiccs Committee
Tuesdayy, 27 August 2013
Professo or Kathryn Refshauge

R
Clinical a
and Rehabiliitation Sciences; Faculty of Health Sc
ciences
Email: kkathryn.refsha
auge@sydne ey.edu.au
ofessor Kath
Dear Pro hryn Refshau
uge,
Your request to mo bove projectt submitted on 28th May 2013 wass considered
odify the ab d by the
Executivve of the Hum
man Researcch Ethics Co
ommittee.
d no ethical objections to the modification/s and has app roved the project
The Committee had p to
proceed.
Details o
of the approvval are as follows:
Project No.: 2012/581
Project Title: Devvelopment oof "neuroche

emical signatures" as a novel diag
gnostic
tech
hnique for h
headache.
Approve
ed Documents:
Date Upploaded Type

T Documeent Name
28/05/20
013 Q
Questionnaire
es/Surveys Headach
he questionnaires
28/05/20
013 A
Advertisemennts/Flyer Web adv
vertisement
Please do not hesiitate to conttact Researcch Integrity (Human Eth

hics) shouldd you require further
informattion or clarificcation.
Yours siincerely
Dr Stephen Assinder
Chair
Human Research Ethics
E Comm
mittee
This H
HREC is con
nstituted an
nd operates in accordan nce with the
e National Heealth and Medical
M
Reseearch Counc
cil’s (NHMRC) National Statement ono Ethical Conduct
C in H
Human Rese earch
(2007
7), NHMRC and
a Universities Austra alia Australia
an Code for the Respon nsible Cond duct of
R
Research (2
2007) and the CPMP/ICHH Note for Guidance
G on Good Cliniical Practice
e.
Research Integrity T +61 2 8627 8111 ABN 15 211 513 464

CRIC
COS 00026A 327
Research Portfolio F +61 2 8627 8177
Level 2, M
Margaret Telfer E ro.huumanethics@sy
ydney.edu.au
The Univeersity of Sydney sydne ey.edu.au
NSW 2006 6 Australia
Research Integrity
Monday, 4 August 2014
Dr Trudy Rebbeck
Clinical and Rehabilitation Sciences; Faculty of Health Sciences
Dear Trudy
I am pleased to inform you that the University of Sydney Human Research Ethics Committee (HREC)
has approved your project entitled “Natural Course and Predictors of Recovery of Migraine and
Other Headache Types”.
Approval Date: 1 August 2014
First Annual Report Due: 1 August 2015
Authorised Personnel: Rebbeck Trudy; Aguila Maria; Brennan Patrick; Lagopoulos Jim;
Leaver Andrew; Refshauge Kathryn;
Documents Approved:
Date Type Document

16/05/2014 Questionnaires/Surveys Disability Assessment Scale
16/05/2014 Questionnaires/Surveys McGill Pain Questionnaire
20/05/2014 Questionnaires/Surveys Headache Disability Questionnaire
20/05/2014 Questionnaires/Surveys Comorbidity Questionnaire
20/05/2014 Questionnaires/Surveys Central Sensitization Inventory
20/05/2014 Questionnaires/Surveys Headache Impact Test
20/05/2014 Questionnaires/Surveys Depression Anxiety Stress Scale
20/05/2014 Questionnaires/Surveys Pittsburgh Sleep Quality Index
20/05/2014 Questionnaires/Surveys Henry Ford Headache Disability Index
20/05/2014 Participant Consent Form Consent Form
21/05/2014 Questionnaires/Surveys International Physical Activity Questionnaire
29/05/2014 Recruitment Letter/Email Recruitment letter to physicians
23/07/2014 Advertisements/Flyer Ad for posting v2
23/07/2014 Participant Info Statement Participant Information Statement v2
23/07/2014 Advertisements/Flyer Web ad v2
23/07/2014 Interview Questions Baseline questions v2

CRICOS 00026A 328
Level 6, Jane Foss Russell E [email protected]
The University of Sydney sydney.edu.au
NSW 2006 Australia
HREC approval is valid for four (4) years from the approval date stated in this letter and is granted
pending the following conditions being met:
Condition/s of Approval
 Continuing compliance with the National Statement on Ethical Conduct in Research Involving
Humans.
 Provision of an annual report on this research to the Human Research Ethics Committee from
the approval date and at the completion of the study. Failure to submit reports will result in
withdrawal of ethics approval for the project.
 All serious and unexpected adverse events should be reported to the HREC within 72 hours.
 All unforeseen events that might affect continued ethical acceptability of the project should be
reported to the HREC as soon as possible.
 Any changes to the project including changes to research personnel must be approved by the
HREC before the research project can proceed.
 Note that for student research projects, a copy of this letter must be included in the
candidate’s thesis.
Chief Investigator / Supervisor’s responsibilities:
1. You must retain copies of all signed Consent Forms (if applicable) and provide these to the HREC
on request.
2. It is your responsibility to provide a copy of this letter to any internal/external granting agencies if
requested.
Yours sincerely
Dr Stephen Assinder
Chair
329
Page 2 of 2
Research Integrity
Tuesday, 30 June 2015
Dr Trudy Rebbeck
Clinical and Rehabilitation Sciences; Faculty of Health Sciences
Dear Trudy
th
Your request to modify the above project submitted on 9 June 2015 was considered by the
Executive of the Human Research Ethics Committee at its meeting on 23rd June 2015.
The additional information provided was reviewed by the Ethics Office on 30th June 2015.
The Committee had no ethical objections to the modification/s and has approved the project to
proceed.
Project Title: Natural Course and Predictors of Recovery of Migraine and Other
Headache Types
Approved Documents:
DATE TYPE DOCUMENT NAME

16/05/2014 Questionnaires/Surveys McGill Pain Questionnaire
20/05/2014 Questionnaires/Surveys Headache Disability Questionnaire
20/05/2014 Questionnaires/Surveys Comorbidity Questionnaire
20/05/2014 Questionnaires/Surveys Central Sensitization Inventory
20/05/2014 Questionnaires/Surveys Headache Impact Test
20/05/2014 Questionnaires/Surveys Depression Anxiety Stress Scale
20/05/2014 Questionnaires/Surveys Pittsburgh Sleep Quality Index
20/05/2014 Questionnaires/Surveys Henry Ford Headache Disability Index
20/05/2014 Participant Consent Form Consent Form
21/05/2014 Questionnaires/Surveys International Physical Activity Questionnaire
21/05/2014 Interview Questions Baseline Questions
16/05/2014 Questionnaires/Surveys Disability Assessment Scale
29/05/2014 Advertisements/Flyer Web advertisement
29/05/2014 Participant Info Statement Participant Information Statement
29/05/2014 Advertisements/Flyer Advertisement for posting
23/07/2014 Advertisements/Flyer Ad for posting v2

CRICOS 00026A 330
Level 2, Margaret Telfer E [email protected]
The University of Sydney sydney.edu.au
NSW 2006 Australia
23/07/2014 Participant Info Statement Participant Information Statement v2
23/07/2014 Advertisements/Flyer Web ad v2
23/07/2014 Interview Questions Baseline questions v2
09/06/2015 Participant Info Statement Participant Information Statement (tracked changes)
09/06/2015 Advertisements/Flyer Advertisement for posting (tracked changes)
09/06/2015 Advertisements/Flyer Web advertisement (tracked changes)
Yours sincerely
Dr Stephen Assinder
Chair
331
Page 2 of 2
APPENDIX 3
Levels of Excitatory and Other Brain Chemicals in Migraine
Detected Using Proton Magnetic Resonance Spectroscopy
Appendix 3 presents supplementary methods and findings for Chapter Three.
332
INTRODUCTION
This report presents the levels of excitatory and other brain chemicals in migraine, to
supplement findings presented in Chapter 3. In Chapter 3, new evidence was presented on
elevated levels of the inhibitory brain chemical, gamma-aminobutyric acid (GABA), in
people with migraine compared to age- and gender- matched controls and on the good
diagnostic accuracy of GABA for classifying individuals with and without migraine. In light
of this new evidence and the hypothesis that migraine pathophysiology involves an imbalance
between excitatory and inhibitory mechanisms (1, 2), levels of excitatory and other brain
neurochemicals in migraine are worth exploring.
Abnormalities in the brain concentrations of N-acetyl-aspartate (NAA), glutamate (Glu),
glutamate + glutamine (Glx), creatine (Cr), choline (Cho), and myoInositol (mI) have been
associated with various pathological changes in the brain. NAA is considered a marker of
neuronal integrity and lower NAA levels are interpreted as neuronal loss or injury (3, 4). Glu
and Glx are associated with excitatory neurotransmission. Cr reflects energy metabolism and
is also used as a reference metabolite in measuring brain chemicals because of its relative
stability across the brain (4). Cho is typically found in cell membranes and is believed to be a
marker of cell turnover. mI maintains glial cell volumes and elevated mI levels are
interpreted as glial activation due to inflammation (5).
Previous studies have investigated these brain chemicals in migraine. For example, decreased
levels of NAA in the cerebellum have been reported in individuals with familial hemiplegic
migraine compared to controls (6). There is also evidence on excitatory abnormalities in
migraine. Elevated levels of Glu have been suggested to be related with central sensitization
mechanisms in animal models of migraine (7). Consistent with this finding, there is evidence
333
for higher Glu levels in the anterior paracingulate cortex of individuals with migraine
compared with controls. Similarly, low ratios of N-acetyl aspartylglutamate and Gln have
been shown in the anterior cingulate cortex and insula in patients with migraine (8).
Alterations in brain chemicals in migraine have also been found in the presence of
comorbidities. For example, elevated levels of mI in the prefrontal cortex were observed in
individuals with migraine and major depressive disorder compared to individuals with
migraine without major depressive disorder(9).Further studies are required to replicateand
validatethese findings to fully understand the neurochemical profile of migraine.
Therefore this report presents the methods and results of proton magnetic resonance
spectroscopy for the following brain chemicals measured during the interictal period from the
same cohort described in Chapter 3: NAA, Glu, Glx, Cr, Cho, and mI. The aim of this report
was to characterise migraine in terms of its neurochemical profile, in addition to the evidence
for GABA presented in Chapter 3.
MAGNETIC RESONANCE SPECTROSCOPY DATA ACQUISITION
Imaging was conducted at the Brain and Mind Research Institute imaging centre on a 3-Tesla
GE Discovery MR750 scanner (GE Medical Systems, Milwaukee, Wisconsin) using an 8-
channel phased array head coil. The protocol comprised three-dimensional sagittal whole-
brain scout for orientation and positioning of all subsequent scans (repetition time, TR=50ms;
echo time, TE=4ms; 256matrix; no averaging, z=5mm thickness). To aid in the anatomical
localisation of all sampled voxels, a T1-weighted Magnetization Prepared RApid Gradient-
Echo (MPRAGE) sequence producing 196 sagittal slices (TR=7.2ms; TE=2.8ms; flip angle =
10°; matrix 256x256; 0.9mm isotropic voxels) was acquired. Next, single voxel 1H-MRS
using a Point RESolved Spectroscopy (PRESS) acquisition with two chemical shift-selective
334
imaging pulses for water suppression was acquired separately from voxels placed in the
thalamus and anterior cingulate cortex using the following parameters: TE=35ms,
TR=2000ms, 128 averages voxel size 2x2x2cm(see Figure 1). Anatomical localisation of
voxel placement was based on the Talairach and Tournoux brain atlas (10) and positioning
was guided by the T1-weighted image. Prior to any post-processing, all spectra were visually
inspected separately by two independent raters to ensure the consistency of the data. Poorly
fitted neurochemical peaks as reflected by large Cramer–Rao Lower Bounds (CRLB) were
excluded from further analysis (CRLB less than 20). Finally, prior to determination of
neurochemical ratios, all spectroscopy data were corrected for grey and white matter and
cerebrospinal fluid content within the acquisition voxel.
335
Thalamus
Anterior Cingulate Cortex
Figure 1. Placement of the single voxel in the thalamus (top panel) and anterior cingulate
cortex (bottom panel) in the (A) axial, (B) coronal, and (C) sagittal planes for
proton magnetic resonance spectroscopy analysis.
All spectra were quantified with the LCModel software package (11, 12) using a PRESS
TE=35 basic set of 15 neurochemicals that included NAA, Glu, Glx, Cr, cho, and mI and
incorporated macromolecule and baseline fitting routines. The radiographers, the
neuroimaging expert who read the spectroscopy data and the neuroradiologist were blinded to
group allocation.
336
Other methods, including study design, participant inclusion, procedures and statistical
analyses have been detailed in Chapter 3.
RESULTS
Spectroscopy data were of sufficient quality to allow analysis from 18 participants each from
the control group and their matched participants in the migraine group.
Profiles of NAA, Glu, Glx, Cr, Cho, and mI in migraine and controls are depicted in
representative spectra in Figure 2. The spectra are plots of signal intensity against the
frequency of the signal. The peaks for the neurochemicals in the spectra therefore represent
the concentration of the neurochemicals, where the height of the peaks is proportional to the
concentration of the neurochemicals (3). Thus the concentrations of NAA, Glu, Glx, Cr, Cho,
and mI in migraine were not significantly different from those in matched controls (Figure 2,
Table 1). Consequently, these brain chemicals also demonstrated poor diagnostic accuracies
in classifying individuals as having migraine or not (Table 2).
Figure 2.Representative spectra from the anterior cingulate cortex of a participant with
migraine (right) and a matched control (left).
337
Table 1. Median and interquartile range of concentrations (in institutional units) of N-acetyl-
aspartate, glutamate, glutamate + glutamine, creatine, choline, and myoInositol in
the thalamus and anterior cingulate cortex in in people with migraine and controls
Migraine Control p values
Thalamus
N-acetyl-aspartate 17.35 (16.06–18.18) 17.59 (16.96–18.14) 0.647
Glutamate 15.84 (14.41–16.87) 16.33 15.18–17.66) 0.215
Glutamate + glutamine 17.08 (15.86–18.22) 17.61 (16.65–18.67) 0.528
Creatine 3.64 (1.35–5.36) 3.71 (2.37–5.26) 0.845
Choline 3.04 (2.77–3.33) 3.12 (2.88–3.44) 0.679
MyoInositol 7.06 (6.18–7.88) 7.10 (6.42–8.09) 0.112
Anterior cingulate cortex
N-acetyl-aspartate 15.28 (14.14–17.60) 15.25 (13.56–16.31) 0.841
Glutamate 21.08 (17.88–23.22) 19.85 (17.93–22.75) 0.478
Glutamate + glutamine 25.63 (22.41–28.05) 24.13 (20.12–28.26) 0.167
Creatine 4.43 (3.13–6.33) 3.84 (3.16–4.58) 0.455
Choline 3.08 (2.74–3.62) 3.35(3.15–3.65) 0.575
MyoInositol 11.32 (10.47–12.37) 11.78 (8.47–12.61) 0.067
338
Table 2. Areas under the curve (95% confidence intervals) from receiver operating
characteristic curve analyses evaluating N-acetyl-aspartate, glutamate, glutamate +
glutamine, creatine, choline, and myoInositol in the thalamus and anterior cingulate
cortex in in people with migraine and controls
Area Under the Curve p values

(95% CI)
Thalamus
N-acetyl-aspartate 0.43 (0.25–0.62) 0.46
Glutamate 0.41 (0.22–0.59) 0.32
Glutamate + glutamine 0.39 (0.21–0.57) 0.24
Creatine 0.51 (0.32–0.70) 0.94
Choline 0.43 (0.24–0.62) 0.46
MyoInositol 0.47 (0.28–0.66) 0.74
Anterior cingulate cortex
N-acetyl-aspartate 0.57 (0.38–0.75) 0.48
Glutamate 0.56 (0.37–0.74) 0.56
Glutamate + glutamine 0.58 (0.39–0.77) 0.41
Creatine 0.61 (0.42–0.79) 0.27
Choline 0.39 (0.20–0.58) 0.24
MyoInositol 0.52 (0.32–0.72) 0.815
__________________________
Abbreviation: CI, confidence interval; ROC, receiver operating characteristic
339
These findings differ from previous reports on brain chemicals in migraine, possibly due to
different methods, region of measurement, and characteristics of the cohort in the studies.
Still, these findings add to the scarce evidence on the neurochemical basis and
pathophysiology of migraine. Considering the elevated levels of GABA detected in the same
migraine cohort, these findings on NAA, Glu, Glx, Cr, Cho, and mI suggest the relative
importance of GABA in the pathophysiology and diagnosis of migraine compared to these
chemicals. Further cross-sectional and longitudinal studies could investigate these brain
chemicals and their changes over time in different brain regions hypothesised to be involved
in migraine, in individuals with migraine with different characteristics from participants of
this study, and during the ictal period.
CONCLUSIONS
Our results demonstrate no significant difference in metabolic profile for NAA, Glu, Glx, Cr,
Cho, and mI in individuals with migraine during the interictal period compared with matched
controls. These findings, taken together with elevated levels of GABA detected in the same
migraine cohort presented in Chapter 3, contribute to the characterisation of the
neurochemical profile of migraine and provide basis to further explore neurochemical
alterations and their probable link with the pathophysiology of migraine.
340
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Trends Neurosci. 2012;35:507–20.
2013;75:365–91.
3. Ulmer S, Backens M, Ahlhelm FJ. Basic principles and clinical applications of
magnetic resonance spectroscopy in neuroradiology. J Comput Assist Tomogr.
2016;40:1–13.
4. Harris RE, Clauw DJ. Imaging central neurochemical alterations in chronic pain with
proton magnetic resonance spectroscopy. Neurosci Lett. 2012;520:192–6.
5. Chang L, Munsaka SM, Kraft-Terry S, Ernst T. Magnetic resonance spectroscopy to
assess neuroinflammation and neuropathic pain. J Neuroimmune Pharmacol.
2013;8:576–93.
6. Zielman R, Teeuwisse WM, Bakels F, Van der Grond J, Webb A, van Buchem MA,
et al. Biochemical changes in the brain of hemiplegic migraine patients measured with
7 tesla 1H-MRS. Cephalalgia. 2014;34:959–67.
7. Oshinsky ML, Luo J. Neurochemistry of trigeminal activation in an animal model of
migraine. Headache. 2006;46:S39-S44.
8. Prescot A, Becerra L, Pendse G, Tully S, Jensen E, Hargreaves R, et al. Excitatory
neurotransmitters in brain regions in interictal migraine patients. MolPain. 2009;5:34–
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9. Lirng J-F, Chen H-C, Fuh J-L, Tsai C-F, Liang J-F, Wang S-J. Increased myo-inositol
level in dorsolateral prefrontal cortex in migraine patients with major depression.
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10. Talairach JT,Tournoux P. Co-planar stereotaxic atlas of the human brain : 3-
dimensional proportional system : An approach to cerebral imaging New York:
Thieme Medical Publishers; 1988.
11. Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R. Simultaneous in vivo
spectral editing and water suppression. NMR Biomed. 1998;11:266–72.
12. Provencher SW. Automatic quantitation of localized in vivo1H spectra with LCModel.
NMR Biomed. 2001;14:260–4.
342
APPENDIX 4
Project Protocol:
Can Neurochemicals Distinguish Headache Types?
Appendix 4 presents the project protocol for studies in Chapters Three and Four.
343
Project Title:
CAN NEUROCHEMICALS DISTINGUISH
HEADACHE TYPES?
Project Protocol
TABLE OF CONTENTS
1.0 Project sequence ................................................................................................................ 2

2.0 Initial telephone screening for participant groups .............................................................. 3
2.1 General screening and demographic details ................................................................ 3
2.2Initial screening for either migraine or control group ..................................................... 3
2.3Telephone screening for inclusion criteria ..................................................................... 4
2.3.1Telephone screening for inclusion criteria for migraine group ......................... 4
2.3.2Telephone screening for inclusion criteria for control group ........................... 5
2.4Telephone screening for exclusion criteria ....................................................................... 6
3.0 Participant forms and questionnaires ................................................................................. 7
3.1Participant information statement and consent form .................................................... 7
3.2Demographic details........................................................................................................13
3.3 Headache duration, location, intensity and frequency ..................................................14
3.4Pain questionnaires ......................................................................................................16
3.4.1Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) .................................... 16
3.4.2Central Sensitization Inventory.................................................... .......................17
3.5Depression Anxiety Stress Scale-21 .............................................................................. 18
3.6Disability questionnaires .............................................................................................. 19
3.6.1Headache Disability Questionnaire ................................................................ 19
3.6.1HIT-6TM Headache Impact Test....................................................................... 20
3.6.2The Henry Ford Headache Disability Index .................................................... 21
4.0 Where do I go for clinical assessment? ............................................................................. 22
5.0 Clinical screening .............................................................................................................. 23
344
1.0 Project Sequence
1.1 Telephone screening (Check if volunteer fulfils inclusion and exclusion criteria)
1.2 Inclusion and enrolment of eligible participants
1.3 Sending of forms and questionnaires
1.3.1 Forms
1.3.1.1 Participant information statement
1.3.1.2 Participant consent form
1.3.1.3 Instructions to get to Brain and Mind Research Institute
1.3.2 Questionnaires
1.3.2.1 Demographic and headache details
1.3.2.2 Short-form McGill Pain Questionnaire-2
1.3.2.3 Central Sensitization Inventory
1.3.2.4 Headache Impact Test-6
1.3.2.5 The Henry Ford Headache Disability Index
1.3.2.6 Headache Disability Questionnaire
1.3.2.7 Depression Anxiety Stress Scales-21
1.4 Schedule for clinical screening and MRI: non-headache day for participants with
migraine
1.5 Clinical screening
1.5.1 Participant examination:
1.5.1.1 Check information on questionnaires for completeness and
confirm details for accuracy
1.5.1.2 Ask other questions, as necessary
1.5.2 Clinical examination:
1.5.2.1 Range of motion measurement
1.5.2.2 Test for mechanosensitivity of neural tissue
1.5.2.3 Spurling's Test
1.5.2.4 Palpation
1.5.2.5 Flexion rotation test
1.5.2.6 Neurological tests
1.5.3 Confirmation of inclusion as participant
1.6 Spectroscopy
345
2.0 Initial telephone screening for patient groups
Potential subjects are recruited by advertisement or from referring doctors as per the ethics
document. Potential subjects will initially be screened over the telephone by either Marilie or
Andrew. During the current (pilot phase) subjects will be recruited with migraine or as controls.
2.1 General screening and demographic details
Name:
Found about study by:

DOB: Gender: F M
Contact: Address:
Phone:
Email:
2.2 Initial screening for either migraine or control group

Have you experienced headaches? Yes  No 
Proceed to Proceed to
1.3 1.4
Telephone Telephone
screening screening
for migraine for control
346
2.3 Telephone screening for migraine
ICHD-II criteria 1.1 Migraine Sample screening question Participant response
without aura
A. At least 5 attacks fulfilling criteria How often do you have headaches?
B-D (Or how many headaches have you have had so far?)
B. Headache attacks lasting 4-72 How long do your headaches typically last?
hours (untreated or unsuccessfully
treated)
C. Headache has at least two of the Can you describe your headache/ how does it feel? (If
following characteristics: needing further prompting: would you describe it as
 Unilateral location sickening?splitting? nauseating?)
 Pulsating quality Where do you feel your headache usually?
 Moderate or severe pain How would you rate the average intensity of your
intensity headacheon a scale of 0 (no pain at all) to 10/10(worst
 Aggravation by or causing possible pain?)
avoidance of routine physical What happens to your headachewith exercise such as
activity (eg walking or climbing walking or climbing stairs? Does it get better or worse?
stairs)
D. During headache at least one of the Do you experience any other symptoms with your
following headache? Can you describe them?
 Nausea and/or vomiting
 Photophobia Or more leading questions:
 Phonophobia Do you ever feel nauseas or vomit when you have a
headache?
Are you sensitive to light or sound during a headache?
(Other info) What do you need to do to relieve your headache and the
other symptoms?
Do you take any medication for your headache? What meds?
What do you think triggers your headaches? (Or more
leading: Do you think your headache is associated with
chocolate intake, alcohol consumption, hormonal changes,
etc.?)
Do you have a family member who has migraine?
E. Not attributed to another disorder Have you been diagnosed with any other condition that may
be related to your headache?
Have you received treatment any other condition that may
ICHD-II criteria 1.1 Migraine with Sample screening question Participant response
aura
A. At least 2 attacks fulfilling criteria How often do you have headaches?
B-D
B. Aura consisting of at least one of Do you experience any other symptoms with your
the following, but headache? Can you describe them?
 No motor weakness;
Do you feel these before or after your headache?
 Fully reversible visual
symptoms Or more leading questions:
o positive features: Do you have visual symptoms with your headache such as
flickering lights, spots or flickering lights, etc.
lines Do you feel pins and needles? Numbness?
o negative features: loss of Does your speech get affected during attacks?
vision
 Fully reversible sensory
symptoms
o positive features: pins
and needles
o negative features:
numbness
 Fully reversible dysphasic
speech disturbance
347
ICHD-II criteria 1.1 Migraine with Sample screening question Participant response
aura
C. At least two of the following: Are your visual symptoms sensory on one side or both
 Homonymous visual sides?
symptoms and/or unilateral How long does it take for the visual / sensory / speech
sensory symptoms symptom (aura) to develop?
 At least one aura symptom How long does the visual / sensory / speech symptom
develops gradually over > (aura) last?
5minutes and/or different
aura symptoms occur in
succession over > 5minutes
 Each symptom lasts > 5 and
less than <60 minutes
D. Headache fulfilling criteria B-D for Once you have the visual / sensory / speech symptom (aura),
migraine without aura begins how long does it take before you get a headache? Can you
during the aura or follows aura describe this headache?
within 60 minutes
(Other info) What do you need to do to relieve your headache and the
other symptoms?
Do you take any medication for your headache? What meds?
What do you think triggers your headaches? (Or more
leading: Do you think your headache is associated with
chocolate intake, alcohol consumption, hormonal changes,
etc.?)
Do you have a family member who has migraine?
E. Not attributed to another disorder Have you been diagnosed with any other condition that may
Have you received treatment any other condition that may
Fulfilled criteria for migraine?

 Yes: Included in migraine group
 No: Excluded
2.4 Telephone screening for controls
2.4.1 Have you had a headache in the past 3 Yes  No 

months?
2.4.2 If you experience headaches, are they Yes  No 

regular? (N.B. “regular” ~ once in 3mos)
2.4.3 Do you experience significant pain? Yes  No 
2.4.4 Do you experience significant neck pain? Yes  No 
2.4.5 Do you have any other chronic Yes  No 

complaints, say pain that lasts for more
than 3 months?
Responded “no” to screening questions 1.4.1 to 1.4.5?

 Yes: Included as control
 No: Excluded
348
2.5 Telephone screening for exclusion criteria
I need to ask a few more questions to make sure that you can undergo MRI scanning.
• Do you have entrapment neuropathy? Yes  No 
Myelopathy?Stent? Epilepsy?
• Are you pregnant? Yes  No 
• Have you had cervical spine surgery? Yes  No 

Whiplash or trauma to the head or neck?
Amputation?
• Do you use a wheelchair? Yes  No 
• Have you had any health complaints in the Yes  No 

last 5 days?
• Have you been diagnosed with severe Yes  No 

depression, since symptoms of depression
influence neurochemistry in the cortical
regions of interest in this study?
• Did you take any medicine for a neck Yes  No 

condition or headache in the previous 6
hours?
• Do you have any metal in your body? This Yes  No 

may be a reason for not going through MRI
scanning. Do you have any metal in your
head? An aneurysm clip? Cochlear implants?
Neurostimulators in your head? Braces on
your teeth? Head tattoos? Metal piercings in
your head? Do you have any metal in your
heart? Have you done any welding, because
that might leave metal in your eyes?
• Do you have claustrophobia or fear of Yes  No 

enclosed spaces? Are you afraid of tight
spaces?
• Do you think you do not have reasonable Yes  No 

command of English to understand
instructions?
Responded “yes” to any of the exclusion criteria?

 Yes: Excluded
 No: Included
349
If individual meets inclusion and exclusion criteria (for either migraine or control), proceed to explain
that they are eligible for study. Explain briefly the following:
• Will you be interested to participate in our project? This is a study about natural
chemicals in your brain that might be associated with different types of headache.
We think there might be different natural chemicals in your brain when you have
migraines and when you do not have migraines. We are doing this study to better
understand these natural chemicals in the brain and maybe eventually better
decide on treatment for headaches.
• You might be interested in the findings
• You will be required to undertake a series of brain scans at the Brain & Mind
Research Institute on Mallett St., Camperdown
If individual has more questions or if he/she is interested to participate in the study, say that
you will send further information and some questionnaires that need to be filled out before
the MRI appointment. These may be sent by email or post, according to preference.
• patient information statement (PIS)
• consent form
• baseline demographic information (other than that collected above)
• baseline questionnaires (SF-MPQ-2, DASS-21, Headache Disability Questionnaire,
Headache Impact Test-6, Headache Disability Inventory)
• information about how to access the BMRI (where to parkand meet etc)
Once participant has had time to read the PIS, explain that we will telephone to book the MRI time.
Remind that he/she should come to the appointment with the questionnaires completed.
350
3.0 Participant forms and questionnaires
3.1 Patient information statement and consent form
PARTICIPANT INFORMATION STATEMENT
Can neurochemicals distinguish headache types?
(1) What is the study about?
You are invited to participate in a study of brain chemicals that are associated with
different types of headache. We will measure the levels of chemicals in different parts
of your brain to determine whether any changes are specific to different types of
headache. You are eligible to participate in this study if you experience frequent
headaches, or you never experience headaches.
You are not eligible to participate if you have any of the following:
• Any disease or injury affecting the neck
• Epilepsy
• A physical condition that prevents you from being positioned in the scanner,
such as being in a wheelchair
• Severe depression
• Any metal in your head or neck, including orthodontic braces for your teeth,
or neck tattoos
• Claustrophobia
If you are not certain whether you are eligible, please ask the researchers. You will have
to complete a questionnaire to ensure there are no contraindications to your
participation. This is routine before any scanning.
(2) Who is carrying out the study?
The study is being conducted by Professors Kathryn Refshauge, Jim Lagopoulos and
Patrick Brennan and Drs Trudy Rebbeck and Andrew Leaver, at The University of
Sydney.
(3) What does the study involve?
You will be required to attend the Brain and Mind Research Institute at Mallett St,
Camperdown, to undertake a series of brain scans. We will first ask you a series of
questions about your headache status and general health. We will then scan your brain
using a particular type of imaging equipment, proton magnetic resonance spectroscopy,
to enable us to measure the concentration of five different chemicals in four regions of
your brain. Some people may experience some mild anxiety when placed in the MRI
scanner. However, the imaging staff involved with this study are trained to deal with
these issues and will be available for immediate support. We will reimburse you for
travel and inconvenience.
351
(4) How much time will the study take?
Your involvement in the study will take 1 hr. We will follow up your progress in 3
months, and measure the level of these chemicals again as well as your headache
status.
(5) Can I withdraw from the study?
Being in this study is completely voluntary - you are not under any obligation to consent
and - if you do consent - you can withdraw at any time without affecting your
relationship with The University of Sydney.
(6) Will anyone else know the results?
All aspects of the study, including results, will be strictly confidential and only the
researchers will have access to information on participants.
A report of the study may be submitted for publication, but individual participants will
not be identifiable in such a report.
(7) Will the study benefit me?
We cannot and do not guarantee or promise that you will receive any benefits from the
study.
(8) Can I tell other people about the study?
You can tell other people about the study. If they are interested in participating, they
would be welcome to ring one of the researchers named on this Participant Information
Sheet.
(9) What if I require further information about the study or my involvement in it?
When you have read this information, one of the chief investigators will discuss it with
you further and answer any questions you may have. If you would like to know more at
any stage, please feel free to contact:
Ms Maria Eliza Aguila

9351 9453
[email protected]
Associate Professor Jim Lagopoulos

93510783
[email protected]
Dr Andrew Leaver
9351 9545
[email protected]
(10) What if I have a complaint or any concerns?
352
Any person with concerns or complaints about the conduct of a research study can
contact The Manager, Human Ethics Administration, University of Sydney on +61 2 8627
8176 (Telephone); +61 2 8627 8177 (Facsimile) or [email protected]
(Email).
353
PARTICIPANT CONSENT FORM
I, ...........................................................................................[PRINT NAME], give consent to my

participation in the research project
TITLE: Can neurochemicals distinguish headache types?
In giving my consent I acknowledge that:
1. The procedures required for the project and the time involved have been explained to me
and any questions I have about the project have been answered to my satisfaction.
2. I have read the Participant Information Statement and have been given the opportunity to
discuss the information and my involvement in the project with the researcher/s.
3. I understand that being in this study is completely voluntary – I am not under any obligation
to consent.
4. I understand that my involvement is strictly confidential. I understand that any research data
gathered from the results of the study may be published however no information about me
will be used in any way that is identifiable.
5. I understand that I can withdraw from the study at any time, without affecting my
relationship with the researcher(s) or the University of Sydney now or in the future.
I consent to:
Receiving Feedback YES  NO 
354
If you answered YES to the “Receiving Feedback” question, please provide your details i.e. mailing
address, email address.
Feedback Option
Address: _______________________________________________________
_______________________________________________________
Email: _______________________________________________________
.................................. ...................................................
Signature
.................................. ....................................................
Please PRINT name
..................................................................................
Date
355
3.2Demographic details
_____________________________________________________________________
Marital status: singleロmarriedロdivorcedロwidowedロ
Highest education level: Primary ロ secondary ロtertiaryロ
Occupation:
Height: Weight:
Medications:
Drug name Dose Frequency Length of time Time/ date last

taken taken
356
3.3Headache duration, location, intensity and frequency
2.3.1 How long have you been experiencing headaches? ______________________ months/ years
Please shade areas on the head and body charts below to indicate where you are currently experiencing pain
including headaches. If you have pain in more than one location, indicate additional locations also.
357
RIGHT LEFT LEFT RIGHT
You should then rate the headache intensity using the following two 0 – 10 scales:
2.3.2 Average headache pain intensity over the last month (Circle the most appropriate)
0 1 2 3 4 5 6 7 8 9 10
No pain Worst possible pain
2.3.3 Average headache intensity over the last 24 hours (Circle the most appropriate)
0 1 2 3 4 5 6 7 8 9 10
No pain Worst possible pain
2.3.4 How often do you experience headaches _________times per month
2.3.5 Global perceived effect

With respect to your headache pain, compared to when you first entered the study, how would you describe
your headaches these days?
(Circle the most appropriate)
-5 -4 -3 -2 -1 0 1 2 3 4 5
Vastly worse Unchanged Completely recovered
358
3.4 Pain questionnaires
Short-Form McGill Pain Questionnaire-2(SF-MPQ-2) 1
This questionnaire provides you with a list of words that describe some of the different qualities of pain and related
symptoms. Please put an X through the numbers that best describe the intensity of each of the pain and related
symptoms you felt during the past week. Use 0 if the word does not describe your pain or related symptoms.
1. Throbbing pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
2. Shooting pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
3. Stabbing pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
4. Sharp pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
5. Cramping pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
6. Gnawing pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
7. Hot-burning pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
8. Aching pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
9. Heavy pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
10. Tender none 0 1 2 3 4 5 6 7 8 9 10 worst possible
11. Splitting pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
12. Tiring-exhausting none 0 1 2 3 4 5 6 7 8 9 10 worst possible
13. Sickening none 0 1 2 3 4 5 6 7 8 9 10 worst possible
14. Fearful none 0 1 2 3 4 5 6 7 8 9 10 worst possible
15. Punishing-cruel none 0 1 2 3 4 5 6 7 8 9 10 worst possible
16. Electric-shock pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
17. Cold-freezing pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
18. Piercing none 0 1 2 3 4 5 6 7 8 9 10 worst possible
19. Pain caused by light none 0 1 2 3 4 5 6 7 8 9 10 worst possible

touch
20. Itching none 0 1 2 3 4 5 6 7 8 9 10 worst possible
21. Tingling or ‘pins and none 0 1 2 3 4 5 6 7 8 9 10 worst possible

needles’
22. Numbness none 0 1 2 3 4 5 6 7 8 9 10 worst possible
1
SF-MPQ-2 © R. Melzack and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 2009. All
Rights Reserved.With permission.
359
CENTRAL SENSITIZATION INVENTORY 2: PART A
Please circle the best response to the right of each statement
1 I feel unrefreshed when I wake up in the Never Rarely Sometimes Often Always
morning
2 My muscles feel stiff and achy Never Rarely Sometimes Often Always
3 I have anxiety attacks Never Rarely Sometimes Often Always
4 I grind or clench my teeth Never Rarely Sometimes Often Always
5 I have problems with diarrhea and/or Never Rarely Sometimes Often Always
constipation
6 I need help in performing my daily activities Never Rarely Sometimes Often Always
7 I am sensitive to bright lights Never Rarely Sometimes Often Always
8 I get tired very easily when I am physically Never Rarely Sometimes Often Always
active
9 I feel pain all over my body Never Rarely Sometimes Often Always
10 I have headaches Never Rarely Sometimes Often Always
11 I feel discomfort in my bladder and/or burning Never Rarely Sometimes Often Always
when I urinate
12 I do not sleep well Never Rarely Sometimes Often Always
13 I have difficulty concentrating Never Rarely Sometimes Often Always
14 I have skin problems such as dryness, itchiness, Never Rarely Sometimes Often Always
or rashes
15 Stress makes my physical symptoms get worse Never Rarely Sometimes Often Always
16 I feel sad or depressed Never Rarely Sometimes Often Always
17 I have low energy Never Rarely Sometimes Often Always
18 I have muscle tension in my neck and shoulders Never Rarely Sometimes Often Always
19 I have pain in my jaw Never Rarely Sometimes Often Always
20 Certain smells, such as perfumes, make me feel Never Rarely Sometimes Often Always
dizzy and nauseated
21 I have to urinate frequently Never Rarely Sometimes Often Always
22 My legs feel uncomfortable and restless when I Never Rarely Sometimes Often Always
am trying to go to sleep at night
23 I have difficulty remembering things Never Rarely Sometimes Often Always
24 I suffered trauma as a child Never Rarely Sometimes Often Always
25 I have pain in my pelvic area Never Rarely Sometimes Often Always
Total =
CENTRAL SENSITIZATION INVENTORY: PART B

Have you been diagnosed by a doctor with any of the following disorders?
Please check the box to the right for each diagnosis and write the year of the diagnosis
No Yes Year Diagnosed
1 Restless leg syndrome
2 Chronic fatigue syndrome
3 Fibromyalgia
4 Temporomandibular joint disorder (TMJ)
5 Migraine or tension headaches
6 Irritable bowel syndrome
7 Multiple chemical sensitivities
8 Neck injury (including whiplash)
9 Anxiety or panic attacks
10 Depression
2From Mayer, T.G.,Neblett, R., Cohen, H., Howard, K.J., Choi, Y.H., Williams, M.J., Perez, Y., &Gatchel, R.J. (2012). The
development and psychometric validation of the Central Sensitization Inventory. Pain Practice, 12(4), 276-285. With
permission.
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3.5 DASS-21
DASS21 Name: Date:
Please read each statement and circle a number 0, 1, 2 or 3 which indicates how much the statement applied to
you over the past week. There are no right or wrong answers. Do not spend too much time on any statement.
The rating scale is as follows:
0 Did not apply to me at all
1 Applied to me to some degree, or some of the time
2 Applied to me to a considerable degree, or a good part of time
3 Applied to me very much, or most of the time
1 I found it hard to wind down 0 1 2 3

2 I was aware of dryness of my mouth 0 1 2 3
3 I couldn't seem to experience any positive feeling at all 0 1 2 3
4 I experienced breathing difficulty (eg, excessively rapid breathing,breathlessness in 0 1 2 3
the absence of physical exertion)
5 I found it difficult to work up the initiative to do things 0 1 2 3
6 I tended to over-react to situations 0 1 2 3
7 I experienced trembling (eg, in the hands) 0 1 2 3
8 I felt that I was using a lot of nervous energy 0 1 2 3
9 I was worried about situations in which I might panic and makea fool of myself 0 1 2 3
10 I felt that I had nothing to look forward to 0 1 2 3
11 I found myself getting agitated 0 1 2 3
12 I found it difficult to relax 0 1 2 3
13 I felt down-hearted and blue 0 1 2 3
14 I was intolerant of anything that kept me from getting on withwhat I was doing 0 1 2 3
15 I felt I was close to panic 0 1 2 3
16 I was unable to become enthusiastic about anything 0 1 2 3
17 I felt I wasn't worth much as a person 0 1 2 3
18 I felt that I was rather touchy 0 1 2 3
19 I was aware of the action of my heart in the absence of physical exertion (eg, sense 0 1 2 3
of heart rate increase, heart missing a beat)
20 I felt scared without any good reason 0 1 2 3
21 I felt that life was meaningless 0 1 2 3
Participants with a score of > 21 on the Depression Scale of on the DASS 21 will be excluded.
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3.6 Headache disability questionnaires
HEADACHE DISABILITY QUESTIONNAIRE
Name:………………………………… Date:………/………./………. Score / 90
Please read each question and circle the response that best applies to you
1. How would you rate the usual pain of your headache on a scale from 0 to 10?
0 1 2 3 4 5 6 7 8 9 10 WORST PAIN
NO
PAIN
2. When you have headaches, how often is the pain severe?
NEVER 1-9% 10-19% 20-29% 30-39% 40-49% 50-59% 60-69% 70-79% 80-89% 90-100% ALWAYS
0 1 2 3 4 5 6 7 8 9 10
3. On how many days in the last month did you actually lie down for an hour or more because of your headaches?
NONE 1-3 4-6 7-9 10-12 13-15 16-18 19-21 22-24 25-27 28-31 EVERY DAY
0 1 2 3 4 5 6 7 8 9 10
4. When you have a headache, how often do you miss work or school for all or part of the day?
NEVER 1-9% 10-19% 20-29% 30-39% 40-49% 50-59% 60-69% 70-79% 80-89% 90-100% ALWAYS
0 1 2 3 4 5 6 7 8 9 10
5. When you have a headache while you work (or school), how much is your ability to work reduced?
NOT 1-9% 10-19% 20-29% 30-39% 40-49% 50-59% 60-69% 70-79% 80-89% 90-100% UNABLE TO
0 1 2 3 4 5 6 7 8 9 10 WORK
REDUCED
6. How many days in the last month have you been kept from performing housework or chores for at least half of the day because of
your headaches?
NONE 1-3 4-6 7-9 10-12 13-15 16-18 19-21 22-24 25-27 28-31 EVERY DAY
0 1 2 3 4 5 6 7 8 9 10
7. When you have a headache, how much is your ability to perform housework or chores reduced?
NOT 1-9% 10-19% 20-29% 30-39% 40-49% 50-59% 60-69% 70-79% 80-89% 90-100% UNABLE
0 1 2 3 4 5 6 7 8 9 10 TO PERFORM
REDUCED
8. How many days in the last month have you been kept from non-work activities (family, social or recreational) because of your
headaches?
NONE 1-3 4-6 7-9 10-12 13-15 16-18 19-21 22-24 25-27 28-31 EVERY DAY
0 1 2 3 4 5 6 7 8 9 10
9. When you have a headache, how much is your ability to engage in non-work activities (family, social or recreational) reduced?
NOT 1-9% 10-19% 20-29% 30-39% 40-49% 50-59% 60-69% 70-79% 80-89% 90-100% UNABLE
0 1 2 3 4 5 6 7 8 9 10 TO PERFORM
REDUCED
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HIT-6TM HEADACHE IMPACT TEST
This questionnaire was designed to help you describe and communicate the way you feel and what you cannot
do because of headaches.
To complete, please check one box for each question.
1.When you have headaches, how often is the pain severe?
Never Rarely Sometimes Very Often Always
2.How often do headaches limit your ability to do usual daily activities including household
work, work, school, or social activities?
3. When you have a headache, how often do you wish you could lie down?
4.In the past 4 weeks, how often have you felt too tired to do work or daily activities because of your headaches?
5.In the past 4 weeks, how often have you felt fed up or irritated because of your headaches?
6. In the past 4 weeks, how often did headaches limit your ability to concentrate on work or daily activities?
COLUMN 1 COLUMN 2 COLUMN 3 COLUMN 4 COLUMN 5

(6 points each) (8 points each) (10 points each) (11 points each) (13 points each)
To score, add points for answers in each column

Please share your HIT-6 results with your doctor.
Total Score: _____________
Higher scores indicate
greater impact on your life.
Score range is 36-78.
Copyright © 2000 QualityMetric Incorporated and Glaxo Wellcome Group Companies. All rights reserved.
HIT-6™ United Kingdom (English) Version 1.0
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3
THE HENRY FORD HEADACHE DISABILITY INVENTORY
Please read carefully: The purpose of the scale is to identify difficulties that you may be experiencing because of your headache. Please check off
“YES”, “SOMETIMES”, or “NO” to each item. Answer each question as it pertains to your headache only.
YES SOMETIMES NO
E1. Because of my headaches I feel handicapped. □ □ □
F2. Because of my headaches I feel restricted in performing □ □ □
my routine daily activities.
E3. No one understands the effect that my headaches have on □ □ □
my life.
F4. I restrict my recreational activities (eg, sports, hobbies) □ □ □
because of my headaches.
E5. My headaches make me angry. □ □ □
E6. Sometimes I feel that I am going to lose control because of □ □ □
my headaches.
F7. Because of my headaches I am less likely to socialize. □ □ □
E8. My spouse (significant other), or family and friends, have □ □ □
no idea what I am going through because of my headaches.
E9. My headaches are so bad that I feel that I am going to go □ □ □
insane.
E10. My outlook on the world is affected by my headaches. □ □ □
E11. I am afraid to go outside when I feel that a headache is □ □ □
starting.
E12. I feel desperate because of my headaches. □ □ □
F13. I am concerned that I am paying penalties at work or at □ □ □
home because of my headaches.
E14. My headaches place stress on my relationships with □ □ □
family or friends.
F15. I avoid being around people when I have a headache. □ □ □
F16. I believe my headaches are making it difficult for me to □ □ □
achieve my goals in life.
F17. I am unable to think clearly because of my headaches. □ □ □
F18. I get tense (eg, muscle tension) because of my □ □ □
headaches.
F19. I do not enjoy social gatherings because of my □ □ □
headaches.
E20. I feel irritable because of my headaches. □ □ □
F21. I avoid traveling because of my headaches. □ □ □
E22. My headaches make me feel confused. □ □ □
E23. My headaches make me feel frustrated. □ □ □
F24. I find it difficult to read because of my headaches. □ □ □
F25. I find it difficult to focus my attention away from my □ □ □
headaches and on other things.
3From Jacobson, G.P., Ramadan, N.M., Aggarwal, S.K., & Newman, C.W. (1994). The Henry Ford Hospital Headache Disability
Inventory (HDI). Neurology, 44, 837-842.With permission.
364
4.0 Where do I go for the MRI?
Please come to the Brain & Mind Research Institute, 94 Mallett Street, Camperdown, where a
member of the research team (Ms. Marilie Aguila, Dr Andrew Leaver or Dr Trudy Rebbeck) will
meet you at the foyer of Building F.
By public transport, get off at Central station, walk to the bus stop Railway Square D, Sydney and
then catch a bus (438, 439, 440, or 461, any bus that will go on Paramatta Road). Get off at
Parramatta Rd NrMallett St. The BMRI is a short walk from there.
If you are driving, there are a number of parking spots on Australia St. near the BMRI that are all
day parking, although these are limited and may be full early.
Contact: Ms Maria Eliza Aguila, T 02 9351 9010, M 0405-756675

Brain & Mind Research Institute T 02 9351 0672
365
4.0 Clinical screening
CLINICAL NOTES for assessing physiotherapist
Subjective Examination
Clarify body chart as provided by patient:
366
Do the painful areas become painful together or separately?
367
History:
• Have you seen a neurologist? Yes  No 
If yes, what was the diagnosis given? ____________________
Yes  No 
• Have you taken any medication to reduce the
pain?
• Have you received physical treatment for the Yes  No 

pain?
If yes, what are these? ____________________
• Have you received alternative treatment for Yes  No 

the pain?
If yes, what are these? ____________________ No 
Pain behaviour:
• Do movements affect your pain? Yes  No 
• Do certain positions affect your pain? Yes  No 
Other: general health etc

• Are you comfortable to go through MRI Yes  No 
scanning?
368
Clinical Examination
Cervical ROM:
Movement Range Comment
Flexion
Extension
Left lateral flexion
Right lateral flexion
Left rotation
Right rotation
Test for Mechanosensitivity of Neural Tissue:

Tests for mechanosensitivity of the upper cervical neural tissues will be done following the protocol
described in Hall &Elvey (2004) In J.D. Boyling& G.A. Jull (Eds.), Grieve's modern manual therapy: The
vertebral column (3rd ed.). (pp. 413-431). Edinburgh: Churchill Livingstone and Hall, T., Briffa, K., & Hopper,
D. (2008). Clinical Evaluation of Cervicogenic Headache: A Clinical Perspective. J Man ManipTher, 16(2):
73–80.
 Yes
 No
Spurling's: Extension/Lateral Flexion: +/- rotation + compression
Positive ロ Negativeロ
Positive Spurling’s?
 Yes: Excluded
 No: Confirm inclusion as participant
Palpation:
Manual examination of the upper cervical joints will be done following the protocol of Zito, Jull & Story,
2006
0/C1 Provoked VAS: Relieved VAS:

C1/C2 Provoked VAS: Relieved VAS:
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Cervical Flexion Rotation Test:
Cervical flexion rotation test will be done following the protocol described in Hall, Briffa, Hopper, &
Robinson, 2010.
Positive ロ Negative ロ
Neurological Tests:
Two or more neurologic signs present?
 Yes: Excluded
 No: Confirm inclusion as participant
370
APPENDIX 5
Project Protocol:
Natural Course and Predictors of Recovery of
Migraine and Other Headache Types
Appendix 5 presents the project protocol for studies in Chapters Five through Seven.
371
Project Title:
NATURAL COURSE AND PREDICTORS OF RECOVERY
OF MIGRAINE AND OTHER HEADACHE TYPES
Project Protocol
TABLE OF CONTENTS
1.0 Project Sequence .................................................................................................................................................3
2.0 Initial telephone screening for participant groups.............................................................................5
2.1Demographic details ...................................................................................................................................5
2.2Initial screening for either headache or control group..............................................................5
2.3Telephone screening for inclusion criteria ......................................................................................5
2.3.1Telephone screening for inclusion criteria for headache groups ......................5
2.3.2Telephone screening for inclusion criteria for control group .............................6
2.4Telephone screening for exclusion criteria .....................................................................................6
2.4.1Telephone screening for exclusion criteria for headache groups......................6
2.4.2Telephone screening for exclusion criteria for control group.............................7
3.0 Participant questionnaires .............................................................................................................................9
3.1Participant information statement and consent form................................................................9
3.2Baseline questions .................................................................................................................................... 13
3.3Pain questionnaires.................................................................................................................................. 17
3.3.1Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) ......................................... 17
3.3.2Central Sensitization Inventory....................................................................................... 19
3.4Disability questionnaires....................................................................................................................... 20
3.4.1HIT-6TM Headache Impact Test ........................................................................................ 20
3.4.2The Henry Ford Headache Disability Index ............................................................... 21
3.4.3Headache Disability Questionnaire ............................................................................... 22
3.4.4Disability Assessment Schedule 2.0............................................................................... 23
3.5Health Questionnaires ............................................................................................................................ 25
3.5.1The Self-Administered Comorbidity Questionnaire .............................................. 25
3.5.2Depression Anxiety Stress Scales – 21 items ............................................................ 26
3.5.3Pittsburgh Sleep Quality Index ........................................................................................ 27
3.5.4International Physical Activity Questionnaire ......................................................... 31
4.0 Where do I go for clinical assessment? ................................................................................................. 37
5.0 Clinical assessment ......................................................................................................................................... 40
5.1Subjective Examination for Headache Groups ............................................................................ 40
5.2Clinical Examination ................................................................................................................................ 42
5.2.1Cervical ROM ............................................................................................................................ 43
372
5.2.2Cervical flexion rotation test ............................................................................................. 46
5.2.3Cranio-cervical flexion test (CCFT) ................................................................................ 47
5.2.4Strength test: Cervical flexors .......................................................................................... 50
5.2.5Endurance test: Cervical flexors...................................................................................... 51
5.2.6Palpation ..................................................................................................................................... 52
5.2.7Cervical extensor test ........................................................................................................... 53
5.2.8Strength test: Cervical extensors .................................................................................... 59
5.2.9Endurance test: Cervical extensors ............................................................................... 60
5.2.10Real-time ultrasound imaging ....................................................................................... 61
5.3Classification of Headache Groups.................................................................................................... 68
5.3.1Checklist for Migraine Group............................................................................................. 68
5.3.2Checklist for Other Non-Migrainous Headaches Group ......................................... 71
5.3.3.1Tension-type headache ................................................................................ 71
5.3.3.2Cervicogenic headache................................................................................. 72
6.0 REDCap headache diary for 6 months ................................................................................................... 74
7.0 Follow up at 1 month, 3 months and 6 months after enrolment .............................................. 74
373
1.0 Project Sequence
1.1 Telephone screening (Check if volunteer fulfils inclusion and exclusion criteria)
1.2 Inclusion and enrolment of eligible participants
1.3 Send questionnaires and forms
1.3.1 Forms
1.3.1.1 Baseline questionnaire (demographic and headache details)
1.3.1.2 Participant information statement
1.3.1.3 Participant consent form
1.3.1.4 Instructions to get to clinical assessment venue
1.3.2 Headache / Pain
1.3.2.1 McGill Pain Questionnaire
1.3.3 Disability
1.3.3.4 WHO Disability Assessment Schedule 2.0
1.3.4 Self-rated Health and Physical Activity
1.3.4.1 Self-Administered Comorbidity Questionnaire
1.3.4.2 Depression Anxiety Stress Scales-21
1.3.4.3 Pittsburgh Sleep Quality Index
1.3.4.4 Long Form International Physical Activity Questionnaire
1.4 Schedule for assessment: preferably 3 days after most recent headache episode
1.5 Baseline Assessment
1.5.1 Participant examination:
1.5.1.1 Check information on questionnaires for completeness and
1.5.1.2 Ask other questions
1.5.2 Clinical examination:
1.5.2.1 Range of motion measurement
1.5.2.2 Flexion rotation test
1.5.2.3 Cranio-cervical flexion test
1.5.2.4 Strength test:Cervical flexors
1.5.2.5 Endurance test: Cervical flexors
1.5.2.6 Palpation of neck structures
1.5.2.7 Cervical extensor test
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1.5.2.8 Strength test : Cervical extensors
1.5.2.9 Endurance test: Cervical extensors
1.5.2.10 Real-time ultrasound imaging
1.5.3 Assignment to groups
1.5.3.1 Migraine
1.5.3.2 Non-migraine
1.5.3.2.1 Tension-type headache
1.5.3.2.2 Cervicogenic headache
1.5.3.2.3 Post-traumatic headache, including persistent headache
attributed to whiplash
1.5.3.3 Mixed or unclassifiable?
1.6 REDCap headache diary for 6 months
1.7 Follow up at 1 month, 3 months and 6 months after enrolment
1.7.1.1 REDCap headache diary
1.7.1.2 McGill Pain Questionnaire
1.7.1.7 WHO Disability Assessment Schedule 2.0
375
2.0 Initial telephone screening for participant groups
Potential participants are recruited by advertisement or from referring doctors as per the ethics
document. Potential participants will initially be screened over the telephone by Marilie (headache
or control groups) and Kanzah (control group).
2.1 Demographic details
Name:
Found about study by:

DOB: Sex: F M
Contact: Address:
Phone:
Email:
Is the volunteer aged 18-65 years old?

 Yes: Proceed to screening for inclusion criteria
 No: Excluded
2.2 Initial screening for either headache or control group
Have you experienced headaches? Yes  No 

Proceed to 2.3.1 Proceed to 2.3.2
Telephone Telephone
screening for screening for
headache groups control
2.3 Telephone screening for inclusion criteria
2.3.1 Telephone screening for inclusion criteria for headache groups
Do you experience recurrent headaches?  Yes  No

Did you experience headache in the last month?  Yes  No
Have you had your headache for more than a year?  Yes  No
Responded “yes” to screening questions 2.3.1?

 Yes: Included in headache group; proceed to screening for exclusion criteria
for headache group
 No: Excluded
376
2.3.2 Telephone screening for inclusion criteria for control group
Have you had a headache in the past 3 months?  Yes  No

If you experience headaches, are they regular? (N.B.  Yes  No
“regular” ~ once in 3mos)
Did you have any recent head or neck surgery?  Yes  No
Do you experience significant neck pain?  Yes  No
Do you have other conditions requiring medical attention or  Yes  No
that affect performance of daily activities (e.g. diabetes
mellitus, malignant cancers, demyelinating, inflammatory and
degenerative neurological conditions, class3 obesity (BMI
>40), severe cardiac or pulmonary disease, infectious or
inflammatory arthropathies)
Do you have severe mobility impairment necessitating  Yes  No
dependence on mobility aids for ambulation?
Responded “no” to screening questions 2.3.2?

 Yes: Included as control; proceed to screening for exclusion criteria for
control group
 No: Excluded
2.4 Telephone screening for exclusion criteria
I need to ask a few more questions to make sure that you are eligible to participate in this research
project.
2.4.1 Telephone screening for exclusion criteria for headache groups
Do you have a known reason for your headache such as  Yes  No

dehydration or a substance or its withdrawal?
Have you not had a craniotomy?  Yes  No
Do you have no access to internet using a computer or a  Yes  No
mobile phone?
Do you have a pacemaker or fibrillator?  Yes  No
Will you not be willing to fill out an online headache diary for  Yes  No
6 months?
Do you think you do not have reasonable command of English  Yes  No
to understand instructions?
Responded “yes” to any of the screening questions 2.4.1?

 Yes: Excluded
 No: Included in headache group
377
2.4.2 Telephone screening for exclusion criteria for control group
I need to ask a few more questions to make sure that you are eligible to participate in this research
project.
Do you have a pacemaker or fibrillator?  Yes  No

Do you think you do not have reasonable command of English  Yes  No
to understand instructions?
Responded “yes” to any of the screening questions 2.4.2?

 Yes: Excluded
 No: Included in control group
378
If the volunteer meets the inclusion and exclusion criteria, proceed to explain that they are eligible
for study. Explain briefly the following:
• Will you be interested to participate in our project? This is a study about
differentiating migraine from other types of headaches. If you experience recurrent
headaches, we will monitor changes in your headaches, and determine what affects
your headaches.
We are doing this study to better understand the similarities and differences between
headache types and maybe eventually to better decide on diagnosis and treatment
for headaches.
• You might be interested in the findings.
• You will be required to undertake a series of clinical tests, including real-time
ultrasound imaging at the Arthritis and Musculoskeletal Research Group Laboratory
at The University of Sydney Cumberland Campus in Lidcombe. If more convenient,
they may also do the assessment at a city clinic(Sydney Specialist Physiotherapy
Centre, Level 1, 50 York St. Sydney).
If the individual has more questions or if he/she is interested to participate in the study, say that you
will send further information and some questionnaires that need to be filled out before the clinical
assessment. These may be sent by email or post, according to their preference.
• participant information statement (PIS)
• consent form
• baseline questionnaire on demographic (and headache information for headache
groups)
• baseline questionnaires
o McGill Pain Questionnaire
o Central Sensitization Inventory
o Headache Impact Test-6
o The Henry Ford Headache Disability Index
o Headache Disability Questionnaire
o WHO Disability Assessment Schedule 2.0
o Self-Administered Comorbidity Questionnaire
o Depression Anxiety Stress Scales-21
o Pittsburgh Sleep Quality Index
o Long Form International Physical Activity Questionnaire
• information about how to get to The University of Sydney Cumberland Campus or
to alternative assessment site (where to parkand meet etc)
Once participant has had time to read the PIS, explain that we will do the assessment, preferably
done within 3 days of the last headache episode of participants with headaches. Inform the
participant that you need the neck and shoulders exposed. Suggest for the participant to come in
singlet. Remind that he/she should come to the appointment with the questionnaires completed.
379
3.0 Participant questionnaires
3.1 Participant information statement and consent form
PARTICIPANT INFORMATION STATEMENT
Distinguishing Migraine from Other Headache Types
(1) What is the study about?
You are invited to participate in a study which will investigate if migraine is different
from other headaches. We will monitor changes in your headaches, and determine
whether physical activity, movement or neck muscle function affects your headache.
This study will also investigate the usefulness of clinical tests to distinguish different
types of headaches.
You are eligible to participate in this study if you experience recurring headaches.
You are not eligible to participate if you have recurring headaches due to dehydration, a
substance or substance withdrawal, if you have had craniotomy, or if you have no
access to internet using a computer or a mobile phone.
If you are not certain whether you are eligible, please ask the researchers.
(2) Who is carrying out the study?
The study is being conducted by Dr Trudy Rebbeck, Dr Andrew Leaver, Mrs Maria
Eliza Aguila, Prof Patrick Brennan, Prof Jim Lagopoulos, and Prof Kathryn
Refshaugeat The University of Sydney.
(3) What does the study involve?
You will be required to attend an assessment session. We will first ask you to answer
some questions about your headache, its effects on your life and general health. We
will then perform a series of clinical tests to analyse your neck muscles and movements.
These tests are part of standard clinical assessment for neck pain. We will also measure
the size of your neck muscles using ultrasound imaging. Images and videos will be
obtained during some of these tests to aid in analysing movements. You will also be
asked to record details of each of your headache episodes such as headache intensity,
duration, triggers, and associated symptoms, over 6 months since your first assessment
using an electronic web-based diary. You will also answer headache and disability
questionnaires at 1 month, 3 months and 6 months after the assessment.
(4) How much time will the study take?
Your involvement in the study will take a maximum of 1.5 hours for the assessment in
the laboratory or clinic. You will then record features of your headache episodes on an
electronic web-based headache diary on days when you have headache for 6 months
after the assessment session. Filling out this diary will take about 10 minutes each
380
time. The headache and disability questionnaires on follow up will take about 20
minutes to answer.
(5) Can I withdraw from the study?
Being in this study is completely voluntary. You are not under any obligation to
consent and, if you do consent, you can withdraw at any time without affecting your
relationship with the investigators or The University of Sydney.
(6) Will anyone else know the results?
All aspects of the study, including results, will be strictly confidential and only the
researchers will have access to information on participants. Images and videos obtained
in this study will be used for purposes of analysis of neck muscles and movements only.
A report of the study may be submitted for publication, but individual participants will
not be identifiable in such a report.
(7) Will the study benefit me?
We cannot and do not guarantee or promise that you will receive any benefits from the
study.
(8) Can I tell other people about the study?
You can tell other people about the study. If they are interested in participating, they
would be welcome to ring one of the researchers named on this Participant Information
Sheet.
(9) What if I require further information about the study or my involvement in it?
When you have read this information, one of the chief investigators will discuss it with
you further and answer any questions you may have. If you would like to know more at
any stage, please feel free to contact:
Ms Maria Eliza Aguila

9351 9010
[email protected]
Dr Trudy Rebbeck
9351 9534
[email protected]
Dr Andrew Leaver
9351 9545
[email protected]
381
(10) What if I have a complaint or any concerns?
Any person with concerns or complaints about the conduct of a research study can
contact The Manager, Human Ethics Administration, University of Sydney on +61 2
8627 8176 (Telephone); +61 2 8627 8177 (Facsimile) or
[email protected] (Email).
This information sheet is for you to keep
382
PARTICIPANT CONSENT FORM
I, ...........................................................................................[PRINT NAME], give consent to my

participation in the research project
TITLE: Distinguishing Migraine from Other Headache Types
In giving my consent, I acknowledge that:
1. The procedures required for the project and the time involved have been explained to me and any
questions I have about the project have been answill bed to my satisfaction.
2. I have read the Participant Information Statement and have been given the opportunity to discuss the
information and my involvement in the project with the researcher/s.
3. I understand that being in this study is completely voluntary – I am not under any obligation to
consent.
4. I understand that my involvement is strictly confidential. I understand that any research data
gathered from the results of the study may be published however no information about me will be
used in any way that is identifiable.
5. I understand that I can withdraw from the study at any time, without affecting my relationship with
the researcher(s) or the University of Sydney now or in the future.
6. I consent to:
• Receiving Feedback YES  NO 
If you answill bed YES to the “Receiving Feedback” question, please provide your details i.e.
mailing address, email address.
Feedback Option
Address: _________________________________________________
_________________________________________________
Email: _________________________________________________
......................................................................................
Signature
.................................. ....................................................
Please PRINT name
..................................................................................
Date
383
3.2 Baseline Questions
3.2.1 Demographic details
PERSONAL DETAILS
1. Name _________________________________________________
2. Sex □ Male □ Female
3. Height (cm) _____________________________________________
4. Weight (kg) _____________________________________________
5. Marital status □ Single □ Married / Defacto
□ Divorced / Widowed / Separated
6. Country of birth ____________________________________
7. Highest education level □ Primary □ Secondary
□ Certificate
□ Diploma or advanced diploma
□ Bachelor degree
□ Graduate
□ Bachelor degree
□ Graduate diploma or graduate certificate
□ Postgraduate degree
8. Occupation ___________________________________________
9. Medications:
Drug name Dose Frequency Length of Time/ date

time taken last taken
384
3.2.2 Headache duration, location, intensity and frequency
QUESTIONS ON HEADACHE
10. How long have you been experiencing headaches? ______________________

months/ years
11. Have you been seen by a health professional for your headaches?
□ Yes □ No
12. Have you been given a headache diagnosis?
□ Yes □ No
If yes,
a. What is your headache diagnosis?

□ Tension-type headache
□ Migraine, please specify ________________
□ Cervicogenic headache
□ Post-traumatic headache, please specify _______________
□ Other, please specify ________________
b. Who diagnosed your headache type?
□ GP □ Neurologist □ Other, please specify ________
385
13. Please shade areas on the head and body charts below to indicate where you
are currently experiencing pain including headaches. If you have pain in more
than one location, indicate additional locations also.
Please proceed to question 14, next page.
RESEARCH TEAM USE ONLY:

Frequency:
Duration:
Intensity:
Associated symptoms:
Triggers:
History:
Previous treatment:
386
You should then rate the headache intensity using the following two 0 – 10 scales:
14. Average headache pain intensity over the last month (Circle the most
appropriate)
0 1 2 3 4 5 6 7 8 9 10
No pain Worst
possible
pain
15. Average headache intensity over the last 24 hours (Circle the most appropriate)
0 1 2 3 4 5 6 7 8 9 10
No Worst
pain possible
pain
16. How many times in a day do you experience headaches? _________times per
day
17. How many times in a month do you experience headaches? ______ times per
month
387
3.3 Pain questionnaires
3.3.1 Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2)
This questionnaire provides you with a list of words that describe some of the different qualities of pain and related
symptoms. Please put an X through the numbers that best describe the intensity of each of the pain and related symptoms
you felt during a typical headache episode. Use 0 if the word does not describe your pain or related symptoms.
1. Throbbing pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
2. Shooting pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
3. Stabbing pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
4. Sharp pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
5. Cramping pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
6. Gnawing pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
7. Hot-burning pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
8. Aching pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
9. Heavy pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
10. Tender none 0 1 2 3 4 5 6 7 8 9 10 worst possible
11. Splitting pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
12. Tiring-exhausting none 0 1 2 3 4 5 6 7 8 9 10 worst possible
13. Sickening none 0 1 2 3 4 5 6 7 8 9 10 worst possible
14. Fearful none 0 1 2 3 4 5 6 7 8 9 10 worst possible
15. Punishing-cruel none 0 1 2 3 4 5 6 7 8 9 10 worst possible
16. Electric-shock pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
17. Cold-freezing pain none 0 1 2 3 4 5 6 7 8 9 10 worst possible
18. Piercing none 0 1 2 3 4 5 6 7 8 9 10 worst possible
19. Pain caused by light touch none 0 1 2 3 4 5 6 7 8 9 10 worst possible
20. Itching none 0 1 2 3 4 5 6 7 8 9 10 worst possible
21. Tingling or ‘pins and none 0 1 2 3 4 5 6 7 8 9 10 worst possible

needles’
22. Numbness none 0 1 2 3 4 5 6 7 8 9 10 worst possible
SF-MPQ-2 © R. Melzack and the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials
(IMMPACT), 2009. All Rights Reserved.
Information regarding permission to reproduce the SF-MPQ-2 can be obtained at www.immpact.org.
388
22. Pulsating none 0 1 2 3 4 5 6 7 8 9 10 worst possible
22. Band-like none 0 1 2 3 4 5 6 7 8 9 10 worst possible
22. Tightness none 0 1 2 3 4 5 6 7 8 9 10 worst possible
22. Excruciating none 0 1 2 3 4 5 6 7 8 9 10 worst possible
389
3.3.2 Central Sensitization Inventory 1: Part A
Please circle the best response to the right of each statement
1 I feel unrefreshed when I wake up in the morning Never Rarely Sometimes Often Always
2 My muscles feel stiff and achy Never Rarely Sometimes Often Always
3 I have anxiety attacks Never Rarely Sometimes Often Always
4 I grind or clench my teeth Never Rarely Sometimes Often Always
5 I have problems with diarrhea and/or constipation Never Rarely Sometimes Often Always
6 I need help in performing my daily activities Never Rarely Sometimes Often Always
7 I am sensitive to bright lights Never Rarely Sometimes Often Always
8 I get tired very easily when I am physically active Never Rarely Sometimes Often Always
9 I feel pain all over my body Never Rarely Sometimes Often Always
10 I have headaches Never Rarely Sometimes Often Always
11 I feel discomfort in my bladder and/or burning Never Rarely Sometimes Often Always
when I urinate
12 I do not sleep well Never Rarely Sometimes Often Always
13 I have difficulty concentrating Never Rarely Sometimes Often Always
14 I have skin problems such as dryness, itchiness, or Never Rarely Sometimes Often Always
rashes
15 Stress makes my physical symptoms get worse Never Rarely Sometimes Often Always
16 I feel sad or depressed Never Rarely Sometimes Often Always
17 I have low energy Never Rarely Sometimes Often Always
18 I have muscle tension in my neck and shoulders Never Rarely Sometimes Often Always
19 I have pain in my jaw Never Rarely Sometimes Often Always
20 Certain smells, such as perfumes, make me feel Never Rarely Sometimes Often Always
dizzy and nauseated
21 I have to urinate frequently Never Rarely Sometimes Often Always
22 My legs feel uncomfortable and restless when I Never Rarely Sometimes Often Always
am trying to go to sleep at night
23 I have difficulty remembering things Never Rarely Sometimes Often Always
24 I suffered trauma as a child Never Rarely Sometimes Often Always
25 I have pain in my pelvic area Never Rarely Sometimes Often Always
Total =
CENTRAL SENSITIZATION INVENTORY: PART B
Have you been diagnosed by a doctor with any of the following disorders?
Please check the box to the right for each diagnosis and write the year of the diagnosis
No Yes Year Diagnosed
1 Restless leg syndrome
2 Chronic fatigue syndrome
3 Fibromyalgia
4 Temporomandibular joint disorder (TMJ)
5 Migraine or tension headaches
6 Irritable bowel syndrome
7 Multiple chemical sensitivities
8 Neck injury (including whiplash)
9 Anxiety or panic attacks
10 Depression
1With permission.From Mayer, T.G., Neblett, R., Cohen, H., Howard, K.J., Choi, Y.H., Williams, M.J.,
Perez, Y., &Gatchel, R.J. (2012).The development and psychometric validation of the Central Sensitization
Inventory.Pain Practice, 12(4), 276-285.
390
3.4 Disability questionnaires
3.4.1 HIT-6TM Headache Impact Test
This questionnaire will be designed to help you describe and communicate the way you feel and what you
cannot do because of headaches.
To complete, please check one box for each question.
2. How often do headaches limit your ability to do usual daily activities including household
work, work, school, or social activities?
3. When you have a headache, how often do you wish you could lie down?
4. In the past 4 weeks, how often have you felt too tired to do work or daily activities because of your
headaches?
5. In the past 4 weeks, how often have you felt fed up or irritated because of your headaches?
6. In the past 4 weeks, how often did headaches limit your ability to concentrate on work or daily
activities?
COLUMN 1 COLUMN 2 COLUMN 3 COLUMN 4 COLUMN 5

(6 points each) (8 points each) (10 points each) (11 points each) (13 points each)
To score, add points for answers in each column

Please share your HIT-6 results with your doctor.
Total Score: ____________________
Higher scores indicate
greater impact on your life.
Score range is 36-78.
© 2001 QualityMetric Incorporated and the GlaxoSmithKline Group of Companies. All rights
reserved.
HIT-6™ US Original (English) Version 1.0
391
3.4.2 The Henry Ford Headache Disability Index 2
Please read carefully: The purpose of the scale is to identify difficulties that you may be
experiencing because of your headache. Please check off “YES”, “SOMETIMES”, or “NO”
to each item. Answer each question as it pertains to your headache only.
YES SOMETI NO
MES
E1. Because of my headaches I feel handicapped. □ □ □
F2. Because of my headaches I feel restricted in performing □ □ □
my routine daily activities.
E3. No one understands the effect that my headaches have on □ □ □
my life.
F4. I restrict my recreational activities (eg, sports, hobbies) □ □ □
because of my headaches.
E5. My headaches make me angry. □ □ □
E6. Sometimes I feel that I am going to lose control because □ □ □
of my headaches.
F7. Because of my headaches I am less likely to socialize. □ □ □
E8. My spouse (significant other), or family and friends, have □ □ □
no idea what I am going through because of my headaches.
E9. My headaches are so bad that I feel that I am going to go □ □ □
insane.
E10. My outlook on the world is affected by my headaches. □ □ □
E11. I am afraid to go outside when I feel that a headache is □ □ □
starting.
E12. I feel desperate because of my headaches. □ □ □
F13. I am concerned that I am paying penalties at work or at □ □ □
home because of my headaches.
E14. My headaches place stress on my relationships with □ □ □
family or friends.
F15. I avoid being around people when I have a headache. □ □ □
F16. I believe my headaches are making it difficult for me to □ □ □
achieve my goals in life.
F17. I am unable to think clearly because of my headaches. □ □ □
F18. I get tense (eg, muscle tension) because of my □ □ □
headaches.
F19. I do not enjoy social gatherings because of my □ □ □
headaches.
E20. I feel irritable because of my headaches. □ □ □
F21. I avoid traveling because of my headaches. □ □ □
E22. My headaches make me feel confused. □ □ □
E23. My headaches make me feel frustrated. □ □ □
F24. I find it difficult to read because of my headaches. □ □ □
F25. I find it difficult to focus my attention away from my □ □ □
headaches and on other things.
2
With permission.From Jacobson, G.P., Ramadan, N.M., Aggarwal, S.K., & Newman, C.W. (1994). The Henry Ford
Hospital Headache Disability Inventory (HDI). Neurology, 44: 837-842.
392
3.4.3 Headache Disability Questionnaire
Name:………………………………… Date:………/………./………. Score / 90
Please read each question and circle the response that best applies to you
1. How would you rate the usual pain of your headache on a scale from 0 to 10?
0 1 2 3 4 5 6 7 8 9 10 WORST PAIN
NO
PAIN
NEVER 1-9% 10-19% 20-29% 30-39% 40-49% 50-59% 60-69% 70-79% 80-89% 90-100% ALWAYS
0 1 2 3 4 5 6 7 8 9 10
3. On how many days in the last month did you actually lie down for an hour or more because of your headaches?
NONE 1-3 4-6 7-9 10-12 13-15 16-18 19-21 22-24 25-27 28-31 EVERY DAY
0 1 2 3 4 5 6 7 8 9 10
4. When you have a headache, how often do you miss work or school for all or part of the day?
NEVER 1-9% 10-19% 20-29% 30-39% 40-49% 50-59% 60-69% 70-79% 80-89% 90-100% ALWAYS
0 1 2 3 4 5 6 7 8 9 10
5. When you have a headache whilst you work (or school), how much is your ability to work reduced?
NOT 1-9% 10-19% 20-29% 30-39% 40-49% 50-59% 60-69% 70-79% 80-89% 90-100% UNABLE TO
0 1 2 3 4 5 6 7 8 9 10 WORK
REDUCED
6. How many days in the last month have you been kept from performing housework or chores for at least half of the
day because of your headaches?
NONE 1-3 4-6 7-9 10-12 13-15 16-18 19-21 22-24 25-27 28-31 EVERY DAY
0 1 2 3 4 5 6 7 8 9 10
7. When you have a headache, how much is your ability to perform housework or chores reduced?
NOT 1-9% 10-19% 20-29% 30-39% 40-49% 50-59% 60-69% 70-79% 80-89% 90-100% UNABLE
0 1 2 3 4 5 6 7 8 9 10 TO PERFORM
REDUCED
8. How many days in the last month have you been kept from non-work activities (family, social or recreational)
because of your headaches?
NONE 1-3 4-6 7-9 10-12 13-15 16-18 19-21 22-24 25-27 28-31 EVERY DAY
0 1 2 3 4 5 6 7 8 9 10
9. When you have a headache, how much is your ability to engage in non-work activities (family, social or
recreational) reduced?
NOT 1-9% 10-19% 20-29% 30-39% 40-49% 50-59% 60-69% 70-79% 80-89% 90-100% UNABLE
0 1 2 3 4 5 6 7 8 9 10 TO PERFORM
REDUCED
393
Page 1 of 2 (12-item, self-administered)
WHODAS 2.0
WORLD HEALTH ORGANIZATION
3.4.4 Disability Assessment Schedule 2.0
12-item version, self-administered
This questionnaire asks about difficulties due to health conditions. Health conditions include
diseases or illnesses, other health problems that may be short or long lasting, injuries, mental
or emotional problems, and problems with alcohol or drugs.
Think back over the past 30 days and answer these questions, thinking about how much
difficulty you had doing the following activities. For each question, please circle only one
response.
.
In the past 30 days, how much difficulty did you have in:
S1 Standing for long periods such as None Mild Moderate Severe Extreme
30 minutes? or
cannot
do
S2 Taking care of your None Mild Moderate Severe Extreme
householdresponsibilities? or
cannot
do
S3 Learning a new task, for None Mild Moderate Severe Extreme
example, learning how to get to a or
new place? cannot
do
S4 How much of a problem did you None Mild Moderate Severe Extreme
have joining in community or
activities (for example, cannot
festivities, religious or other do
activities) in the same way as
anyoneelse can?
S5 How much have you been None Mild Moderate Severe Extreme
emotionallyaffected by your or
health problems? cannot
do
Please continue to next page...
394
Page 2 of 2 (12-item, self-administered)
WHODAS 2.0
WORLD HEALTH ORGANIZATION
DISABILITY ASSESSMENT SCHEDULE 2.0
In the past 30 days, how much difficulty did you have in:
S6 Concentrating on doing None Mild Moderate Severe Extreme
something forten minutes? or cannot
do\
S7 Walking a long distance such None Mild Moderate Severe Extreme
as akilometre [or equivalent]? or cannot
do
S8 Will behing your whole body? None Mild Moderate Severe Extreme
or cannot
do
S9 Getting dressed? None Mild Moderate Severe Extreme
or cannot
do
S10 Dealing with people you do None Mild Moderate Severe Extreme
not know? or cannot
do
S11 Maintaining a friendship? None Mild Moderate Severe Extreme
or cannot
do
S12 Your day-to-day work? None Mild Moderate Severe Extreme
or cannot
do
H1 Overall, in the past 30 days, how many dayswill be Record number of days
these difficulties present? _____
H2 In the past 30 days, for how many days will be you
Record number of days
totally unableto carry out your usual activities or work
_____
because of any health condition?
H3 In the past 30 days, not counting the days that you will
be totally unable, for how many days did you cut back Record number of days
or reduce your usual activities or work because of any _____
health condition?
This completes the questionnaire. Thank you.
395
3.5 Health Questionnaires
3
3.5.1 The Self-Administered Comorbidity Questionnaire
Instructions:
The following is a list of common problems. Please indicate if you currently have the problem in the first
column. If you do not have the problem, skip to the next problem.
If you do have the problem, please indicate in the second column if you receive medications or some other type
of treatment for the problem.
In the third column indicate if the problem limits any of your activities.
Finally, indicate all medical conditions that are not listed under “other medical problems” at the end of the page.
Do you have the Do you receive Does it limit your
problem? treatment for it? activities?
No Yes  No Yes No Yes
PROBLEM
(0) (1) (0) (1) (0) (1)
Heart disease N Y N Y N Y
High blood pressure N Y N Y N Y
Lung disease N Y N Y N Y
Diabetes N Y N Y N Y
Ulcer or stomach disease N Y N Y N Y
Kidney disease N Y N Y N Y
Liver disease N Y N Y N Y
Anemia or other blood disease N Y N Y N Y
Cancer N Y N Y N Y
Depression N Y N Y N Y
Osteoarthritis, degenerative arthritis N Y N Y N Y
Back pain N Y N Y N Y
Rheumatoid arthritis N Y N Y N Y
Other medical problems

(please write in)
N Y N Y N Y
N Y N Y N Y
3
With permission.From Sangha O, Stucki G, Liang MH, Fossel AH, Katz JN. The Self-Administered
Comorbidity Questionnaire: A new method to assess comorbidity for clinical and health services research.
Arthritis Rheum. 2003 Apr 15;49(2):156-63. PubMed PMID:12687505 .
396
3.5.2 Depression Anxiety Stress Scales – 21 items
DASS21 Name: Date:
Please read each statement and circle a number 0, 1, 2 or 3 which indicates how much the statement applied to you over the
past week. There are no right or wrong answers. Do not spend too much time on any statement.
The rating scale is as follows:
0 Did not apply to me at all
1 Applied to me to some degree, or some of the time
2 Applied to me to a considerable degree, or a good part of time
3 Applied to me very much, or most of the time
1 I found it hard to wind down 0 1 2 3

2 I will be aware of dryness of my mouth 0 1 2 3
3 I couldn't seem to experience any positive feeling at all 0 1 2 3
4 I experienced breathing difficulty (eg, excessively rapid breathing,breathlessness in the 0 1 2 3
absence of physical exertion)
5 I found it difficult to work up the initiative to do things 0 1 2 3
6 I tended to over-react to situations 0 1 2 3
7 I experienced trembling (eg, in the hands) 0 1 2 3
8 I felt that I will be using a lot of nervous energy 0 1 2 3
9 I will be worried about situations in which I might panic and makea fool of myself 0 1 2 3
10 I felt that I had nothing to look forward to 0 1 2 3
11 I found myself getting agitated 0 1 2 3
12 I found it difficult to relax 0 1 2 3
13 I felt down-hearted and blue 0 1 2 3
14 I will be intolerant of anything that kept me from getting on withwhat I will be doing 0 1 2 3
15 I felt I will be close to panic 0 1 2 3
16 I will be unable to become enthusiastic about anything 0 1 2 3
17 I felt I will ben't worth much as a person 0 1 2 3
18 I felt that I will be rather touchy 0 1 2 3
19 I will be aware of the action of my heart in the absence of physical exertion (eg, sense of heart 0 1 2 3
rate increase, heart missing a beat)
20 I felt scared without any good reason 0 1 2 3
21 I felt that life will be meaningless 0 1 2 3
397
Page 1 of 4
Participant’s Initials AM
Participant ID __________ Date ______________ Time ________
____ PM
3.5.3 Pittsburgh Sleep Quality Index
INSTRUCTIONS:
The following questions relate to your usual sleep habits during the past month only. Your
answers should indicate the most accurate reply for the majority of days and nights in the past
month. Please answer all questions.
1 During the past month, what time have you usually gone to bed at night?
BED TIME ___________
2 During the past month, how long (in minutes) has it usually taken you to fall asleep each
night?
NUMBER OF MINUTES ___________
3 During the past month, what time have you usually gotten up in the morning?
GETTING UP TIME ___________
4 During the past month, how many hours of actual sleep did you get at night? (This may
be different than the number of hours you spent in bed.)
HOURS OF SLEEP PER NIGHT ___________
For each of the remaining questions, check the one best response. Please answer all questions.
5 During the past month, how often have you had trouble sleeping because you . . .
a) Cannot get to sleep within 30 minutes
Not during the past Less than once a Once or twice a Three or more times a
month____ week ____ week ____ week ____
b) Wake up in the middle of the night or early morning
c) Have to get up to use the bathroom
398
Page 2 of 4
d) Cannot breathe comfortably
e) Cough or snore loudly
f) Feel too cold
g) Feel too hot
h) Had bad dreams
i) Have pain
j) Other reason(s), please describe _________________________________________________
___________________________________________________________________________
How often during the past month have you had trouble sleeping because of this?
6 During the past month, how would you rate your sleep quality overall?
Very good ____________
Fairly good ____________
Fairly bad ____________
Very bad ____________
399
Page 3 of 4
7 During the past month, how often have you taken medicine to help you sleep (prescribed
or "over the counter")?
8 During the past month, how often have you had trouble staying awake whilst driving,
eating meals, or engaging in social activity?
9 During the past month, how much of a problem has it been for you to keep up enough
enthusiasm to get things done?
No problem at all ____________
Only a very slight problem ____________
Somewhat of a problem ____________
A very big problem ____________
10 Do you have a bed partner or room mate?
No bed partner or room mate ____________
Partner/room mate in other room ____________
Partner in same room, but not same bed ____________
Partner in same bed ____________
If you have a room mate or bed partner, ask him/her how often in the past month
you have had...
a) Loud snoring
b) Long pauses between breaths whilst asleep
c) Legs twitching or jerking whilst you sleep
400
Page 4 of 4
d) Episodes of disorientation or confusion during sleep
e) Other restlessness whilst you sleep; please describe

________________________________________________________________________
___________________________________________________________________________
© 1989, University of Pittsburgh. All rights reserved. Developed by Buysse,D.J.,

Reynolds,C.F., Monk,T.H., Berman,S.R., and Kupfer,D.J. of the University of Pittsburgh
using National Institute of Mental Health Funding.
Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ: Psychiatry Research, 28:193-
213, 1989.
401
3.5.4 International Physical Activity Questionnaire
We are interested in finding out about the kinds of physical activities that people do as part of
their everyday lives. The questions will ask you about the time you spend being physically
active in a usual week. Please answer each question even if you do not consider yourself to
be an active person. Please think about the activities you do at work, as part of your house
and yard work, to get from place to place, and in your spare time for recreation, exercise or
sport.
Think about all the vigorous and moderate activities that you do in a usual week. Vigorous
physical activities refer to activities that take hard physical effort and make you breathe much
harder than normal. Moderate activities refer to activities that take moderate physical effort
and make you breathe somewhat harder than normal.
PART 1: JOB-RELATED PHYSICAL ACTIVITY
The first section is about your work. This includes paid jobs, farming, volunteer work, course
work, and any other unpaid work that you do outside your home. Do not include unpaid work
you might do around your home, like housework, yard work, general maintenance, and caring
for your family. These are asked in Part 3.
1. Do you currently have a job or do any unpaid work outside your home?
Yes
No Skip to PART 2: TRANSPORTATION
The next questions are about all the physical activity you do on a usual weekas part of your
paid or unpaid work. This does not include traveling to and from work.
2. On a usual week, on how many days do you do vigorous physical activities like heavy
lifting, digging, heavy construction, or climbing up stairsas part of your work? Think
about only those physical activities that you do for at least 10 minutes at a time.
_____ days per week
No vigorous job-related physical activity Skip to question 4
3. How much time do you usually spend on one of those days doing vigorous physical
activities as part of your work?
_____ hours per day

_____ minutes per day
402
4. Again, think about only those physical activities that you do for at least 10 minutes at a
time. During ausual week, on how many days do you do moderate physical activities
like carrying light loads as part of your work? Please do not include walking.
_____ days per week
No moderate job-related physical activity Skip to question 6
5. How much time do you usually spend on one of those days doing moderate physical
activities as part of your work?
_____ hours per day

6. On a usual week, on how many days do you walk for at least 10 minutes at a time as
part of your work? Please do not count any walking you do to travel to or from work.
_____ days per week
No job-related walking Skip to PART 2: TRANSPORTATION
7. How much time do you usually spend on one of those days walking as part of your work?
_____ hours per day

PART 2: TRANSPORTATION PHYSICAL ACTIVITY
These questions are about how you traveled from place to place, including to places like
work, stores, movies, and so on.
8. On a usual week, on how many days do you travel in a motor vehicle like a train, bus,
car, or tram?
_____ days per week
No traveling in a motor vehicle Skip to question 10
9. How much time do you usually spend on one of those days traveling in a train, bus, car,
tram, or other kind of motor vehicle?
_____ hours per day

403
Now think only about the bicycling and walking you might do to travel to and from work, to
do errands, or to go from place to place.
10. On a usual week, on how many days do you bicycle for at least 10 minutes at a time to
go fromplace to place?
_____ days per week
No bicycling from place to place Skip to question 12
11. How much time do you usually spend on one of those days to bicycle from place to
place?
_____ hours per day

12. During a usual week, on how many days do you walk for at least 10 minutes at a time to
go from place to place?
_____ days per week
No walking from place to place Skip to PART 3:

HOUSEWORK, HOUSE
MAINTENANCE, AND
CARING FOR FAMILY
13. How much time do you usually spend on one of those days walking from place to place?
_____ hours per day

PART 3: HOUSEWORK, HOUSE MAINTENANCE, AND CARING FOR FAMILY
This section is about some of the physical activities you might do in a usual week in and
around your home, like housework, gardening, yard work, general maintenance work, and
caring for your family.
14. Think about only those physical activities that you do for at least 10 minutes at a time. On
a usual week, on how many days do you do vigorous physical activities like heavy
lifting, chopping wood, shoveling snow, or digging in the garden or yard?
_____ days per week
No vigorous activity in garden or yard Skip to question 16
404
activities in the garden or yard?
_____ hours per day

16. Again, think about only those physical activities that you did for at least 10 minutes at a
time. On a usual week, on how many days do you do moderate activities like carrying
light loads, sweeping, will behing windows, and raking in the garden or yard?
_____ days per week
No moderate activity in garden or yard Skip to question 18
activities in the garden or yard?
_____ hours per day

18. Once again, think about only those physical activities that you do for at least 10 minutes
at a time. On a usual week, on how many days do you do moderate activities like
carrying light loads, will behing windows, scrubbing floors and sweeping inside your
home?
_____ days per week
No moderate activity inside home Skip to PART 4:

RECREATION, SPORT AND
LEISURE-TIME PHYSICAL
ACTIVITY
activities inside your home?
_____ hours per day

405
PART 4: RECREATION, SPORT, AND LEISURE-TIME PHYSICAL ACTIVITY
This section is about all the physical activities that you do in a usual week solely for
recreation, sport, exercise or leisure. Please do not include any activities you have already
mentioned.
20. Not counting any walking you have already mentioned, on a usual week, on how many
days do you walk for at least 10 minutes at a time in your leisure time?
_____ days per week
No walking in leisure time Skip to question 22
21. How much time do you usually spend on one of those days walking in your leisure time?
_____ hours per day

22. Think about only those physical activities that you do for at least 10 minutes at a time. On
a usual week, on how many days do you do vigorous physical activities like aerobics,
running, fast bicycling, or fast swimming in your leisure time?
_____ days per week
No vigorous activity in leisure time Skip to question 24
activities in your leisure time?
_____ hours per day

24. Again, think about only those physical activities that you did for at least 10 minutes at a
time. On a usual week, on how many days do you do moderate physical activities like
bicycling at a regular pace, swimming at a regular pace, and doubles tennis in your
leisure time?
_____ days per week
No moderate activity in leisure time Skip to PART 5: TIME

SPENT SITTING
406
activities in your leisure time?
_____ hours per day
PART 5: TIME SPENT SITTING
The last questions are about the time you spend sitting whilst at work, at home, whilst doing
course work and during leisure time. This may include time spent sitting at a desk, visiting
friends, reading or sitting or lying down to watch television. Do not include any time spent
sitting in a motor vehicle that you have already told me about.
26. On a usual week, how much time do you usually spend sitting on a weekday?
_____ hours per day

27. On a usual week, how much time do you usually spend sitting on a weekend day?
_____ hours per day

This is the end of the questionnaire, thank you for participating.
407
4.0 Where do I go for clinical assessment?
Please come to the Arthritis and Musculoskeletal Research Group Laboratory (AMRG Lab)
on the second floor of S Block, Room 218 of the University of Sydney (Cumberland
Campus) in Lidcombe. The address of University of Sydney (Cumberland Campus) is 75
East Street, Lidcombe NSW 2141.
A member of the research team (Ms. Marilie Aguila, Dr Andrew Leaver or Dr Trudy
Rebbeck) will meet you at the receiving area of the AMRG Lab which you will find as soon
as you enter S218.
Here are some suggestions to get to the Cumberland campus by public transport:
By train
The nearest railway station to the Cumberland campus is Lidcombe station. It takes
approximately 20-30 minutes to walk to campus from the station. We recommend using the
available bus services.
By bus
• The Metrobus M92 service (Parramatta to Sutherland via Cumberland Campus)

• The 915 bus (Lidcombe/TAFE/University) service.
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Bus stop locations
• From Lidcombe Station: On the eastern Commonwealth Bank side
• From Cumberland Campus: Going to Lidcombe, the bus stop is located outside
Gate 1. Travelling from Lidcombe station or towards Bankstown the bus stop is on
East Street, located on the opposite side of road from the campus between Gates 1 &
2.
If you are driving, there are a number of parking spots inside the campus.
Current visitor parking fees are $5.00 per entry for Gate 2 & $4.00 per day for Gate 3.
Contact: Ms Marilie Aguila T 02 9351 9010 M 0405-756675
409
Alternative clinical assessment venue:
Sydney Specialist Physiotherapy Centre
Level 1, 50 York Street, Sydney 2000
Please refer to http://www.transportnsw.info/ for trip planning and public transportation

timetables.
410
5.0 Clinical assessment
5.1 Subjective Examination

5.1.1 Check information on baseline questionnaire for completeness and
5.1.2 Other questions: general health etc.:
1. Do you have headache today?  Yes  No
If yes:
When did it start? How long has this episode been going on? _____________
How would you describe the headache? ______________________________
How would you rate the intensity of the headache on a scale of 0 to 10, 0
being no pain and 10 being the worst possible pain? _______________
2. When will be your last headache episode?

_______________________________________
3. How long does a headache episode last if it is untreated or if it is not successfully treated?
Minimum _____ hours ______ minutes
Maximum _____ hours ______ minutes
4. Does your headache go away  Yes  No

between episodes?
5. What symptoms accompany your headaches?

Does it always come with your headache?
How would you rate the intensity of that symptom?(Mild? Moderate? Severe?)
Accompanying symptoms How often Intensity

Never Occasionally Often Mild Moderate Severe
Nausea
Vomiting
Light sensitivity
Noise sensitivity
Lightheaded/dizzy
Unsteadiness
Blurred vision
Eye swelling
Loss of appetite
Yawning
Fatigue
Confused thinking
Other.______________________
6. Do you have neck pain or stiffness  Yes  No
411
with your headache
7. Do you feel any sensation for a period of minutes to an hour before the onset of your
headache?
a. visual aura (e.g. blind spots, flashing or zigzag lights) □ Yes□ No
b. feeling of pins/needles or numbness □ Yes□ No
c. feeling of weakness □ Yes□ No
d. feeling of difficulty speaking □ Yes□ No
If you have any of these aura symptoms, can you describe how long each symptom
lasts? _______________________________________________________________
8. What do you think causes your headache or makes it worse?
a. Certain foods (e.g. chocolate, cheeses) 

b. Alcohol (e.g. red wine, beer, spirits) 
c. Awkward head or neck postures or neck movement 
d. Sustained neck postures (e.g. reading) 
e. Pressure over the neck or base of skull on the headache side 
f. Medication 
g. Routine physical activity or walking stairs 
h. Lifestyle factors (e.g. excessive sleep, fasting or dieting) 
i. Exercises/sports 
j. Environmental factors (e.g. strong odours, smoke, weather 
changes)
k. Stress or anxiety 
l. Fatigue 
m. Hormonal changes 
n. Other. Please describe_____________________________ 
o. Does not know what brings on headache / Does not see any 
pattern
9. Do you know what started your headache?

What do you think started your headache?
Does not know 

Knows what started headache (Please describe below) 
_____________________________________________________________
412
10. What relieves your headache?
a. Medication(Are these the same ones you listed on the baseline 

questionnaire?)
b. Heat/ice applications 
c. Physical activity 
d. Neck exercise or change of position 
e. Alcohol 
f. Relaxation 
g. Massage 
h. Sleeping/rest 
i. Unknown 
j. Other. Please describe ________________________________ 
11. Have you received physical  Yes  No

treatment for your headache?
If yes, what are these? ____________________________________
12. Have you received alternative  Yes  No

treatment for your headache?
If yes, what are these? ____________________________________
13. Have you been diagnosed with any  Yes  No

other condition that may be related
to your headache?
14. Have you had any imaging or  Yes  No

laboratory test done on your neck?
If yes, what will be the test and what will be the result?
__________________________
15. Do other members of your family suffer from similar headaches?
 Yes (please specify relation)  No  Unsure

________________________
16. Are you comfortable to go through clinical  Yes  No

tests typically done forneck pain?
17. Are you comfortable to go through  Yes  No

ultrasound imaging?
18. Are you willing to fill out an online  Yes  No

headache diary for 6 months?
5.2 Clinical Examination

413
5.2.1 Cervical ROM
Procedure for Measuring Neck Motion with the CROM (Reproduced from CROM Procedure
Manual)
“The CROM Instrument is aligned on the nose bridge and ears and is fastened to the head
by a Velcro strap (see Figure 1).The rotation meter is magnetic and responds quickly to the
shoulder-mounted magnetic yoke, accurately measuring cervical rotation. Because the
rotation meter is controlled by the magnetic yoke, shoulder substitution is eliminated.
Figure 1. CROM with rotation arm and magnetic yoke
Three dial angle meters are used to take most of the measurements. The sagittal plane meter
and the lateral flexion meter are gravity meters. The rotation meter is magnetic and
responds quickly to the shoulder-mounted magnetic yoke, accurately measuring cervical
rotation. Because the rotation meter is controlled by the magnetic yoke, shoulder substitution
is eliminated.
Cervical Flexion and Extension

Instruct the participant to sit erect in astraight-back chair sitting upright with the sacrum
against the back of the chair, the thoracic spine away from the back of the chair, arms
hanging at sides and feet flat on the floor. Next, instruct the participant to position the CROM
instrument as if putting on a pair of glasses. Ensure the CROM sitting on ears. Fasten the
Velcro straps snuggly in line with the bows. You will not need the magnetic yoke, rotation
armforward head arm or vertebra locator for these measurements.
To assure full flexion in this multi-joint area, the participant

should start in neutral posture.First,instruct the participant to
“bring your chin to your chest as far as you can comfortably
go” (suboccipital flexion). Then ask “Can you go any
further?” in order toobtain full cervical flexion(see Figure 2).
To take the reading on the sagittal plane meter, read through
the meter’s beveled edge; from this angle the pointer will be
magnified to the dial edge. Record this measurement in the
appropriate space on the recording sheet.
To measure cervical extension, first instruct the participant to

414
Figure 2: Cervical flexion
“Look up to the ceiling as far as you comfortably can. Then have the participant extend
further until full extension is achieved. “Can you go any further?” Record this measurement
also.
Lateral Flexion
Instruct the participant to sit erect on a straight-back chairwith the sacrum against the back of
the chair, thethoracic spine away from the back of the chair, arms hanging at sides and feet
flat on the floor. To eliminate rotation during lateral flexion, the participant should focus on a
point on a wall straight ahead. The sagittal plane meter will read zero if the participant is
looking straight ahead. The lateral flexion meter will also read zero if the head is not laterally
flexed. If the lateral flexion meter does not read zero, record the reading as lateral flexion at
rest. You will not need the magnetic yoke, rotation arm, forward head arm nor vertebra
locator for these measurements.
Instruct the participant to flex the head laterally to the left, keeping the shoulders level and
without rotating the head (see Figure 3). Monitor for shoulder elevation by lightly placing
your hand on the right shoulder, and correct manually any head motion outside the coronal
plane. Note and record the measurement from the lateral flexion meter.
Now instruct the participant to flex the head laterally to the right, again keeping the shoulders
level without rotating the head (see Figure 4). As before, monitor for left shoulder elevation
and correct head motion. Note and record the measurement from the lateral flexion meter.
Figure 3: Left lateral flexion Figure 4: Right lateral flexion
415
WARNING: The magnetic yoke should not be used if the participant has an implanted
pacer or defibrillator.
Rotation
You will need to use the CROM instrument plus the magnetic yoke and rotation arm for these
measurements. To obtain an accurate rotation measurement, first determine which direction is
north. (You can find magnetic (map) north by noting the direction of the red needle on the
rotation meter when it is at least four feet from the magnetic yoke.)
Next, place the magnetic yoke on the participant’s shoulders with the arrow pointing
north.(See Figure 5.)
Figure 5: Magnetic yoke pointing north
Instruct the participant to sit erect on a straight-back chair with the sacrum against the back of
the chair, the thoracic spine away from the back of the chair, arms hanging at sides and feet
flat on the floor. The lateral flexion and sagittal plane meters must read zero for the rotation
meter to be level; if necessary, assist the participant into the correct position. As the
participant faces straight ahead, grasp the rotation meter between your thumb and index
finger and turn the meter until one of the pointers is at zero.
Instruct the participant to focus on a horizontal line on the wall so the head is not tipped
during rotation. Ask participant to straighten up if required. Have the participant turn the
head as far to the left as possible (see Figure 6), and to ensure that no shoulder rotation
occurs, lightly stabilize the right shoulder with your hand. (Note: if the head and shoulders
are rotated together the pointer will not move because the magnetic yoke positioned on the
shoulders eliminates shoulder substitution). Record this measurement in the appropriate place
on the recording sheet.
Whilst you lightly stabilize the left shoulder, instruct the participant to turn the head as far as
possible to the right (see Figure 7). Record this measurement also.”
416
Figure 6: Left rotation Figure 7: Right rotation
Movement Range (degrees) Comment

Flexion
Extension
Left lateral flexion
Right lateral flexion
Left rotation
Right rotation
5.2.2 Cervical flexion rotation test

NOTE: Do the flexion rotation test using the CROM device.
Cervical flexion rotation test will be done following the protocol described in Hall T,
Robinson K (2004) 4.
The cervical flexion rotation test assesses dysfunction at the C1-C2 segment (Hall &
Robinson, 2004)4. This test will be done following the protocol of Stratton and Bryan (1994)
as described by Hall and Robinson (2004)4 and using the CROM to measure the range of
passive cervical rotation.
The participant is asked to wear the CROM device and lies supine and relaxed. The patient’s
head is pre-positioned so that the cervical spine is in end range of flexion. Keeping the
4
Hall T, Robinson K (2004) The flexion-rotation test and active cervical mobility—A comparative
measurement study in cervicogenic headache. Man Ther 9:197–202.
417
cervical spine maximally flexed, the head is then passively rotated to the left and the right.
The assessor then instructs the participant as follows: “Let me do all the work. You just have
to relax and let me know if the movement produces or increases pain or headache”. End of
range is at that point when a firm resistance is felt by the assessor or when the participant
complains of pain or headache, whichever comes first. It is important to do this test with the
least provocation of headache or other related symptoms. The examinerthen measures of the
range of rotation to determinewhether the FRT is positive or negative.
A positive test is defined where the range of movement at which restriction, pain or headache
sets in is ≤ 32o.5.
 Positive Left: ______ degrees  Negative
Right: ______ degrees
5.2.3 Cranio-cervical flexion test (CCFT)

Cranio-cervical flexion test will be done following the protocol of Jull et at., 20086
This will be done in two stages.
Stage 1: Analysis of performance of the craniocervical flexion (CCF) action.
The participant is positioned in supine, crook lying with theirears aligned with the shoulder or
parallel with the plinth. Initially, check that participant has the range passively—hence the
examiner performs passive CCF first. The dial should increase to at least 30mmHg. Ensure
the movement is NOT provocative of headache symptoms to proceed. If provocative of
symptoms, DO NOT proceedwith the test. Note that sometimes if you adjust the participant
position to slightly elevate shoulders, the test may become asymptomatic (presumably
because reducing stretch on sensitive neural tissue).
Instruct the participant to “Slowly slide the back of your head up the bed to nod your
chin.”The examiner analyses the movement to ensure that it is head rotation with negligible
activity in the sternocleidomastoid or anterior scalene muscles. This movement is analysed by
observing and/or palpating the activity in the superficial flexors during the flexion.
5
Ogince M, Hall T, Robinson K (2007) The diagnostic validity of the cervical flexion-rotation test in C1/2-
related cervicogenic headache. Man Ther 12:256–262.
6
Jull GA, O'Leary SP, Falla DL (2008) Clinical assessment of the deep cervical flexor muscles: The
craniocervical flexion test. J Manipulative PhysiolTher 31:525–533.
418
Then ask the participant to do this movement using the
pressure biofeedback unit (PBU). The PBU is partially
inflated and positioned such that its top is on the back of
the head (Figure 8). With the participant in starting
position, inflate the PBU to 20mmHg. Ask the
participant to do the nodding movement to elevate the
target pressure from 20 to 22 mmHg (top of red/pink
band).
Figure 8. Participant starting position for CCFT
Signs of abnormal muscle behaviour or activation patterns of the deep cervical flexors are as
indicated below, and the corrective strategies in the adjacent column.
Abnormal Action Corrective Cues
Retraction strategy: Head rotation does not Passively correct the movement pattern by
increase with increases in pressure targets moving the participant’s head through
and the movement becomes more a head craniocervical flexion.
retraction action than craniocervical flexion
Early activation of SCM: Superficial Use the following verbal cues: “eye look
cervical flexors are overly active especially down”, “Look at the ceiling and slowly look
at the early stage of the movement down to just above your knees”
Compensation with hyoid muscles. Inhibit activity of the hyoid muscles using
this verbal cue: “Put your tongue on the roof
of your mouth, lips together and teeth
apart)”
The head does not return to the starting First, check the cuff position and inflation
position. This is indicated on the dial by of the PBU. Make sure the top edge of the
being less than or greater than 20mmHg. cuff is just under the occiput. Make sure that
the cuff is inflated adequately.
Second, check head position. Is this due to a

lack of proprioception? Passively move the
participant’s head to neutral or to the
starting position and then check the cuff
reading again
419
Record the reason for ‘failure of the test’ and verbally or manually correct the action. Allow
the participant 1-2 repetitions to correct the action then proceed to stage 2.
Stage 2: Testing isometric endurance of the deep cervicalflexors at test stages that the
participant is able to achieve withthe correct craniocervical flexion action.
Proceed with this stage when the participant can correctly perform the craniocervical flexion
movement. Otherwise, provide corrective cues to address the abnormal action.
The participantdoes the head nod action to 22mmHg and holds the head nod for 5 seconds. If
the participant canperform at least 3 repetitions of 5-second holds withoutsubstitution
strategies, the test is progressed to the nextpressure target.Repeat the process in 2 mmHg
increments, until 30 mmHg. Use “top of green band” as cue for 24 mmHg, top of yellow
band for 26 mmHg, top of blue band for 28 mmHg, and black line next to blue band for 30
mmHg. At each stage, make sure that the correct head nod action is done for all pressure
increments and that no substitutions are occurring, and the SCM or AS are not overly active.
Once a level is reached when the participant cannot hold the head nod for 5 seconds for
repetitions (eg 26mmHg), go back to the previous level (eg 24mmHg). Ask the participant to
do 10- second hold at this pressure increment for 3 repetitions.If the participant can perform
as many repetitions of 10-second holds of the head nod without substitution strategies.
The examiner should watch out for signs of reduced endurance of the deep cervical flexors
during the head nod: the superficial flexor muscles are overly active, the head is jerky despite
holding the neck in flexion, the pressure of the PBU is not held steady and/or decreases.
Record the pressurelevel(s) that the participant can hold steady for 10 seconds and the
number of repetitions at that level, with minimal superficial muscle activity and without
substitution strategies.If the test will be not performed because of provocation of headache,
record accordingly.
22 mmHg: Number of repetitions of 10 sec-hold a: ________
24 mmHg: Number of repetitions of 10 sec-hold: ________
 Unable to do test
a
Must be able to do at least 3 good repetitions to progress to the next pressure target
420
5.2.4 Strength test: Cervical flexors
Maximal isometric force in the neck flexor and extensor muscles will be measured using the
Lafayette Manual Muscle Tester (Model 01163) handheld dynamometer using a protocol by
Silvermann et al 1991 7, also described in Dumas et al., 2001 8.This technique has been shown
to have good reliability (ICC>0.74). Two trials will be done and the highest score will be
used for statistical analysis.
The participant will be positioned supine, with the chin nodded (that is, maintaining
craniocervical neutral). The examiner places his/her hand under the participant’s occiput at
the beginning of the test. The participant is instructed to lift the head just off the examiner’s
hand by gently pushing against the dynamometer then pushing progressively harder whilst
the examiner holds the device still (isometric hold, make test). Contraction is held for about
3–5 seconds (or until the dynamometer beeps twice). Two trials will be done with adequate
rests between trials.
The mean of both repetitions will be used for statistical analysis.
Strength Test Force (kg) Comment

Trial 1 Trial 2 Highest Score
Neck flexors
7
Silverman JL, Rodriquez AA, Agre JC (1991) Quantitative cervical flexor strength in healthy subjects and in
subjects with mechanical neck pain. Arch Phys Med Rehabil 72:679–681.
8
Dumas JP, Arsenault AB, Boudreau G, Magnoux E, Lepage Y, Bellavance A, Loisel P. (2001) Physical
impairments in cervicogenic headache: traumatic vs. nontraumatic onset. Cephalalgia 21:884–893.
421
5.2.5 Endurance test: Cervical flexors
Cervical flexor endurance will be measured following the protocol of Harris et al., 2005 9;
also cited in Edmonston et al., 2008 10.
This technique will be appropriate for participants with headaches showed excellent test-
retest reliability (ICC = 0 93) when used with individuals with postural neck pain 9.
The test will be performed with the participant in crook-lying on a plinth, with hands on the
abdomen (Figure 9).
Figure 9. Starting position for endurance test of

the neck flexors
Guide the participant’s head through slight upper neck flexion (head nod). The amount of
flexion is just enough so that the head lifts about 2.5 cm above the plinth. After two trials and
with the participant able to do the correct movement, the participant is ready to do the test.
The examiner then places his/her hand on the plinth just below the occiput. The
participantslowly flexes his or her upper neck and lifts his or her head just off the examiner's
handwhilst retaining the upper neck flexion (Figure 10).
Figure 10. Head position for endurance test of

the neck flexors
9
Harris KD, Heer DM, Roy TC, Santos DM, Whitman JM, Wainner RS (2005) Reliability of a measurement of
neck flexor muscle endurance. Physical therapy 85:1349–1355.
10
Edmondston SJ, Wallumrød ME, Macléid F, Kvamme LS, Joebges S, Brabham GC (2008) Reliability of
isometric muscle endurance tests in subjects with postural neck pain. J Manipulative PhysiolTher 31:348–354.
422
Verbal feedback to maintain the head in slight flexion is provided (“tuck your chin in” or
“hold your head up”). The test will be terminated if the participant is unable to maintain the
flexed position, or is limited by exacerbation of pain or headache or discomfort,or at 1
minute, whichever comes first. The holding time will be measured in minutes and seconds.
Endurance Test Time (mins:secs) Comment

Neck flexors
5.2.6 Palpation
Manual examination of the upper cervical joints will be done following the protocol of
Maitland, 1982 11 and Zito, Jull & Story, 2006 12.
Participant position: Participant is in prone with forehead resting on one palm (hands
overlapped) and neck positioned in neutral mid-flexion-extension position.
Examiner position: Standing at the head of the treatment table.
Palpate the suboccipital area overlying and superior to the atlas with the tips of the middle
three fingers. To do this, the pressure of the finger tips should be directed towards the
participant's eyes and the tissue should be palpated by both a medial-lateral movement and a
postero-anterior movement (Figure 11).
Figure 11. Palpation of the suboccipital area
Continue palpation by using the full length of the pads of the middle and ring fingers of each
hand in the laminar-trough area (that is from the lateral surface of spinous process to the
lateral margin of the articular pillar), from C1 to C4. The technique involves moving both
11
Maitland GD (1982) Palpation examination of the posterior cervical spine: The ideal, average and
abnormal.Aust J Physiother 28:3–12.
12
Zito G, Jull G, Story I (2006) Clinical tests of musculoskeletal dysfunction in the diagnosis of cervicogenic
headache. Man Ther 11:118–129.
423
hands in rhythm with each other, moving the skin up and down with the pads of the fingers as
far as the skin allows, whilst gently sinking into the muscle bellies and other soft tissue. The
purpose is to feel for areas of thickness, swelling and tightness in the soft tissue and also for
abnormalities of the general bony contour. Perform two or three up and down movements in
the upper cervical area, then slide the fingers caudally 2 or 3 centimetres and the process is
repeated until the level of C4 is reached.
Once the general andmore gross impression has been gained through the full pads of the
fingers, the procedure should be repeated but this time using the tip of the pad of only one
finger of each hand.
Ask the participant if any of the movements provoke or relieve the headache. Then ask the
participant to rate any local or referred pain provoked during the manual examinationat any
joint. The participant then rates the pain using a 0–10 verbal analogue scale, where 0 is no
pain and 10 is the worst pain possible.
Headache provoked?  Yes  No
If yes, at which level?  0/C1 VAS:
 C1/C2 VAS:
 C2/C3 VAS:
 C3/C4 VAS:
5.2.7 Cervical extensor test
Cervical extensor test will be performed as described on page 213 of Jull G, Sterling M, Falla
D, Treleaven J, O’Leary S. (2008)13.
Background
Cervical muscle behaviour is commonly assessed in people with neck pain. Reliable
protocols for cervical flexor motor performance have been established and there is increasing
body of evidence supporting the coexistence of neck pain and cervical flexor muscle
behavioure.g. 14. Whilst protocols for measuring cervical extensor muscle endurance and
13
Jull G, Sterling M, Falla D, Treleaven J, O’Leary S. (2008). Whiplash, headache, and neck pain: research-
based directions for physical therapies. Churchill Livingstone/Elsevier, Edinburgh.
14
O’Leary S, Falla D, Jull G (2011)The relationship between superficial muscle activity during the cranio-
cervical flexion test and clinical features in participants with chronic neck pain. Manual Therapy 16:452-455.
424
strength have been established e.g. 15, to date, reliable protocols for assessing cervical extensor
motor control have not.
Associations between deep extensor (multifidus) muscle cross sectional area and motor
activation of the lumbar multifidus and pain have been demonstrated in participants with
lower back pain 16. This same association is believed by some clinicians to be a feature of
neck pain, but has yet to be demonstrated.
Deep Extensor Muscle Behaviour

Cervical Extensor Test
The cervical extensor test will be performed as described by Jull et al (2008) 17. This test is
understood to bias activation of the deep cervical extensors (namely the semispinalis cervicis
and multifidus groups) with some validity obtained under fMRI 18. The cervical extensor test
will be scored through video analysis of the performance of the participant according to
maintenance of the start position, eccentric phase and concentric phase. The following scores
will be reported: Overall score, Phase 1 (Maintenance of start position) score,Phase 2
(Eccentric phase) score, Phase 3 (Concentric phase) score, and aggregate score which is the
total of the phase scores. The participant is required to expose the neck, upper back and
shoulder. A singlet top will provide sufficient exposure.
Start position
The participant will be instructed on adopting a prone position on the plinth with their head
over the edge of the bed (see Figure 12).The participant is instructed on holding this position
for 10 seconds then performing a slow neck flexion (see Figure 13) and extension procedure
without involving head extension beyond neutral.
Instruction (Video filming commences)
Participant instructions
One standard instruction will be issued to the participant: “I will place your head in a
position called the start position. Look at a point directly below your head on the floor. Can
you hold this position for 10 seconds first then perform the movement. The movement to
perform is to curl your neck slowly downwards so that you are looking underneath the plinth,
then slowly curl your neck back up to the start position without lifting your chin. Ensure you
15
16
Hides JA, Stokes MJ, Saide MJ, Jull GA, Cooper DH (1994) Evidence of lumbar multifidus muscle wasting
ipsilateral to symptoms in patients with acute/subacute low back pain. Spine 19:165.–172.
17
Jull G, Sterling M, Falla D, Treleaven J, O’Leary S. (2008). Whiplash, headache, and neck pain: research-
based directions for physical therapies. Churchill Livingstone/Elsevier, Edinburgh (beginning page. 213).
18
O'Leary S, Cagnie B, Reeve A, Jull G, Elliott JM (2011) Is there altered activity of the extensor muscles in
chronic mechanical neck pain? A functional magnetic resonance imaging study.Archives of physical medicine
and rehabilitation 92:929–934.
425
finish so that your eyes are looking at the ground where they started.” The participant will be
given verbal feedback and manual correction for two test movements.
The participant will be asked to repeat this 10 times.
Testing
The participant assumes the “Start Position” with manual and verbal correction by the
examiner as required.
The participant will be asked to hold the starting position for 10 seconds. The “hold time”
will be recorded by the assessor using a stopwatch. The assessor will count each second of
this period aloud. At the conclusion of the “hold time”, the assessor will repeat the
instructions through each stage of the test movement.
“Look at a point directly below your head on the floor.
Now slowly curl your neck downwards so that you are looking underneath the plinth.
Now slowly curl your neck back up to the start position without lifting your chin.
Your eyes should be looking at the same point on the ground as where they started.
Now repeat 10 times.”
The assessor then counts each repetition that the participant performs.(Video filming
concludes.)
Figure 12: Start position (Phase 1) Figure 13: Neck flexion during Phase 2
(eccentric phase)
Video Analysis
Concurrent video analysis will be conducted. The video camera will be positioned on a tripod
perpendicular to the participant to obtain a lateral view. The distance between the camera and
the participant, tripod height, camera inclination and zoom setting will be standardised.
Ensure that the legs of the plinth (at the head of the plinth) and the tripod are on their
designated markers on the floor.
426
Optimal settings to be determined
Camera distance Position the head at start position in centre grid of camera screen
Tripod height (As set)
Camera inclination Position the head at start position in centre grid of camera screen
Zoom 100%
Rate overall performance using the following scale:

Normal 9-10 repetitions of correct pattern
Mostly normal: 5-8 repetitions of correct pattern
Mostly abnormal 1-4 repetitions of correct pattern
Abnormal Unable to perform 1 repetition correctly
Number of repetitions until failure (loss of optimal motor performance) _________out of 10
Overall performance  Normal  Mostly  Mostly  Abnormal

normal abnormal
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Assessment Notes:
Rating of each phase: Encircle the cell that describes the performance at each phase.
Phase 1: Maintenance of start position

0 1 2 3 Comment
Maintains Mostly Mostly does Definitely Drifts into Flexion
start position maintains not maintain does not Drifts into UCE
start position position maintain start
position
Phase 2: Eccentric phase

0 1 2 3 Comment
Normal Mostly Mostly Abnormal Forward translation of head
control normal abnormal Dominant CCF motion
Movement is jerky or quick
Full range of neck flexion
not achieved
Phase 3: Concentric phase

0 1 2 3 Comment
Normal Mostly Mostly Abnormal Head not returned to starting
control normal abnormal position
Low cervical spine not
returned to the starting
position
Dominant CCE motion
Movement is jerky or quick
428
Cause of failure, if any (Tick all that apply, based on video.)
 Lower cervical spine drifts into flexion at starting position
 Forward translation of the head during eccentric phase
 Movement is jerky during eccentric phase
 Participant does not lift head back up to start position during concentric phase
 The head returns to the starting position by the low cervical spine remains in flexion
(sags) during concentric phase
 Inability to maintain a neutral craniocervical flexion/extension position
 Participant in a position of craniocervical extension through or at the end of repetition
 Visually prominent semispinalis capitis muscle
 Other: (Please describe.) _______________________________________________
Failure of optimal motor performance of this task is understood to occur for many reasons.
Some of the reasons suggested are outlined in the following table with description of how this
will appear visually.
Table. Common reasons for failure of the CET
Reason for failure Description

1. Starting Position
Lower cervical spine drifts into flexion An inability to maintain a neutral cervical spine
posture against gravity i.e., the lower cervical
spine will sag into flexion
2. Eccentric Phase
Forward translation of the head Participant cannot control flexion of the lower
cervical spine against gravity (eccentric
extensor action). Instead the head translates
downward rather than curling downward.
Movement is jerky
3. Concentric Phase
Return of head position Participant does not lift head back up to start
position as they fatigue. A difference of 5
degrees is considered not returning to the start
position.
Return of low cervical spine position The head returns to the starting position but the
low cervical spine remains in flexion (sags)
4. Overall Performance
Dominance of craniocervical extension Inability to maintain a neutral craniocervical
action flexion/extension position, participant in a
position of craniocervical extension through or
at the end of repetition. Visually prominent
semispinalis capitus muscle
Number of repetitions of accurate
performance
429
5.2.8 Strength test: Cervical extensors
Cervical extensor strength will be measured using a Lafayette Manual Muscle Tester (Model
01163) handheld dynamometer using a protocol similar to that used by Silvermann et al
1991 19 also described in Dumas et al., 200120. This technique has been shown to have good
reliability (ICC>0.74).
The participant lies in prone. The dynamometer is placed on the back of the head. The
participant will be asked to lift his or her head off the bed. The examiner will place his or her
hand under the participant’s forehead to ensure the head remains off the bed for the test. The
participant will be asked to first gently push against the dynamometer then to push
progressively harder whilst the examiner holds the device still (isometric hold, make test).
Contraction will be performed against the dynamometer for about 3-5s (until dynamometer
beeps twice). Two trials will be done.
The mean of both repetitions will be used for statistical analysis.
Strength Test Force (kg) Comment

Trial 1 Trial 2 Highest Score
Neck
extensors
19
Silverman JL, Rodriquez AA, Agre JC (1991) Quantitative cervical flexor strength in healthy subjects and in
subjects with mechanical neck pain. Arch Phys Med Rehabil 72:679–681.
20
Dumas JP, Arsenault AB, Boudreau G, Magnoux E, Lepage Y, Bellavance A, Loisel P. (2001) Physical
impairments in cervicogenic headache: traumatic vs. nontraumatic onset. Cephalalgia 21:884–893.
430
5.2.9 Endurance test: Cervical extensors
Cervical extensor endurance will be measured following the protocol of Edmonston et al
2008 21.
The endurance test for the cervical extensors is a modification of a test described
byLjungquist et al (1999) 22, also adapted from the Biering-Sorensen lumbar extensor test.
The participantwill lie in prone with the head over the edge of the plinth. Arms are kept to the
side. The examiner supports the participant’s head A strap will be placed at the level of T6 to
support theupper thoracic spine. A band will be fixed aroundthe head with a fluid
inclinometer attached to the band overthe occiput. A 2-kg weight will be suspended from
theheadband so that the weight will be located just short of thefloor. The participant's head
will be positioned in neutral position and the test begins when the examiner removes the
support of the participant's head. (see Figure 14).
Figure 14. Starting position for endurance

test for the cervical extensors
The participantholds the cervical spine horizontal with the chinretracted. The test is
terminated if the neck position changes by more than 5° from the horizontalas measured by
the inclinometer, or if the participant could no longer hold the position due to pain or
discomfort, or at 3 minutes and 20 seconds, whichever comes first. Theholding time will be
measured in minutes and seconds.
Endurance Test Time (mins:secs) Comment

Neck extensors
21
22
Ljungquist T, Fransson B, Harms‐Ringdahl K, Björnham Å, Nygren Å (1999) A physiotherapy test package
for assessing back and neck dysfunction—Discriminative ability for patients versus healthy control subjects.
Physiotherapy Research International 4:123–140.
431
5.2.10 Real-time ultrasound imaging
Measurement of cervical multifidus using real time ultrasound
Configuration of the ultrasound machine

For the measurement of cervical multifidus, a 5-10MHz transducer (adjusted to 5MHz for big
build, 7.5 MHz for medium build, and 10MHz for small build) transducer is used to make
measurements of muscle size and shape (VF 8- 3 +); depth is set at 4cm (may need to adjust
for a larger neck size i.e. 5 cm) and focus adjusted to the level of the midpoint of the muscle.
Gain, dynamic range, TGC and contrast is adjusted to optimise visualisation of the fascial
planes.
Participant positioning
A standardised position of the participant is to be ensured for reproducibility of
measurements across participants. The participant is seated in a chair with the feet flat on the
floor facing the bed. The participant’s head is rested on pillows.
Identification of the cervical multifidus

The spinous process of the C4level is identified by palpation and marked with a pen.
Imaging of the neck

Imaging of the neck is carried out by placing the transducer perpendicular to the long axis of
the posterior neck at the C4 level. The left and right side of the neck is imaged separately by
sliding the transducer left/right until an image is obtained where the spinous process is
horizontally level with the uppermost part of the articular pillar. Multifidus is identified by
the following landmarks: inferiorly the bony outline of the lamina, laterally by the facet joint,
superiorly by the fascial plane, medially by the spinous process. The clearest image is
ensured by maintaining the transducer 90 degrees to the fascia of the underlying muscle or
varying the tilt of the transducer until the clearest fascial plane is present. In the presence of
two facial planes, measurements are taken from the facial plane closest in level to the spinous
process.
432
Measurements
• Lateral dimension
The lateral dimension is measured as the distance between the echogenic spinous
process/highest point of the spinous process and the point where the two fascial planes meet
adjacent to the supero/medial border of the facet.
• Antero-posterior dimension
The anterior-posterior dimension is measured by bisecting the lateral distance, measuring

from leading edge to leading edge-top edge of fascial plane superiorly (lower of the two
when two present), to the top edge of the lamina (brightest part).
• How to use the equipment: Siemens RTUS machine

1. Press power button
2. Allow a few minutes for machine to start
3. Press New participant
4. To choose “neck” protocol, go to exam and double click “NECK”
5. Enter participant data
6. Press ok
7. This will take you to “Live image”
8. Apply a liberal amount of gel on the transducer head
9. Place transducer over spinous process at C4 level
10. When ready, press “Freeze” and then “Print store” to capture the image
11. Then place the transducer over the cervical multifidus at C4 level on the
left side
13. Turn menu button (central) x1 to left
14. Choose “clip capture”
15. Scroll down far left toggle to “time capture”
16. Choose 8 secs by scrolling toggle up
17. Adjust clip speed if necessary on left button corner of screen
18. Keep the transducer on the cervical multifidus and ask the participant to
lift his/her head off the pillow, and capture this image by pressing
“Freeze” and then “Clip store”.
right side
“Freeze” and then “Clip store”.
22. To create new participant data, press “live screen” and repeat steps 3-5
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23. To retrieve clip, go to participant data (2nd button top left on key board)
and click on latest entry
24. To save image on USB, plug in USB (port is located at the back of
machine on right), USB will appear on screen under “export/import”
Neck Protocol Pre-set Parameters:

VF 8 3+ Persist 4
Neck R/S 3
36 dB Map 3
7.3 MHz Tint 1
DR 55dB DTCE Med
Edge 2 32 fps
• Instructions for measuring

• Measuring D1: Lateral dimension
1. Press calliper first, then move the mouse to place on the echogenic
spinous process/highest point of the spinous process, not past the
convexity of the spinous process. Note, at times the best frame may not
display the spinous process on the screen, with it being on the edge or just
off the screen. If this is the case, choose the highest point of the spinous
process at the point it leaves the screen or follow the lamina up.
2. Press set.
3. Move calliper using the mouse to the second pointwhere the two fascial
planes meet adjacent to the supero/medial border of the facet, medial to
the convex curve of the facet joint. Note, you may follow the lamina up to
the facet joint to reach this same point.
4. Press set.
5. This will display as D1 on the screen. Record this in the table provided.
• Measuring D2: Bisecting point of D1
6. Calculate (D1)/2 (i.e. ½ the D1 distance)

7. Press calliper and place on one of the lateral dimension points
8. Press set.
9. Follow the lateral dimension line across by the distance measured in step
6.
10. Press set.
11. This will display as D2 on the screen. Record this in the table provided.
• Measuring D3: Perpendicular bisector of D1
12. Press calliper and place on the D2 point which halves the D1 line (the
point from step 9).
13. Press set.
14. Move the mouse down to the top edge of the lamina (highest brightest
part). This will be close to the fascial layer for rotatores.
15. Press set.
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16. This will display at D3. Record this in the table provided.
• Measuring D4: ‘Shortest’ AP dimension (closest to multifidus AP dimension)
17. Press calliper then move the mouse to the top edge of the lamina (highest
brightest part) at the point perpendicularly below your D2 point (the
bottom of the D3 line).
18. Press set
19. Move the calliper using the mouse along the D3 line until you meet
theleading edge (top edge) of the first facial plane that you can see,
usually situated close to the D1 line or in line with the facet joint and
spinous process. This first facial plane will not be present on all video
clips. If this is the case, simply record N/A or comment in the table
provided.
20. Press set.
21. This will display as D4. Record this in the table provided. If the first facial
plane is not present in the clip, simply record N/A or comment in the table
provided.
• Measuring D5: “Longest” AP dimension (closest to multifidus plus semi-

spinalis)
22. Press calliper and move the mouse to the top edge of the lamina (highest
brightest part), the same point as in step 17.
23. Press set.
24. Move the calliper using the mouse to the leading edge (top edge) of the
first fascial plane that you see above the facet joint or spinous process.
Note, in some video clips, there may be two fascial planes (quite close
together) present above the facet joint or spinous process.
25. Press set.
26. This will display as D5. Record this using the table provided.
• Measuring contracted dimensions:
27. Click patient browser again. This should display the original clip.
 Choosing the frame: Muscle contracted
28. Watch the clip once more to determine when multifidus is contracting.
29. Move the clip to the time given in the table. The time is located at the top
of the screen, next to the date.
 Measuring D1–D5 FOR CONTRACTED STATE
30. Repeat steps 1–26.
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• Data collection_RTUS cervical multifidus EXAMPLE:
Left Right
Relaxed Contracted Relaxed Contracted
Lateral dimension
Antero-posterior dimension (D4)
Antero-posterior dimension (D5)
Muscle shape (Lat / AP)
Multiplied linear dimension

(Lat x AP)
436
• How to use the equipment: GE Logiq Portable Ultrasound Machine
1. Press power button (top centre of keyboard)
2. Allow a few minutes for machine to start
3. Press “New Patient” (left side of control panel).
4. A login window will appear. Leave the password blank and move the
trackball to “log on”. Press “Set /B Pause” button (lower right off centre of
control panel) to select “log on” on screen.
5. Enter participant data: Patient ID, Last Name, First Name. If these cells are
not blank, move trackball to “New Patient” on screen and then press “Set
/B Pause” button (lower right off centre of control panel)
6. Check that Category on left side of screen has “Small Parts” depressed.
7. Press “New Patient” button on control panel again. This will take you to
the live image screen.
8. Check that the following parameters are correct:
• Neck (protocol)
• B mode
• Fq 8.0Hz
• Gn 62
• E/A 3/2
• Map N/0
• D 3.0cm
• DR 66
• FR 65Hz
• AO 100%
9. Apply a liberal amount of gel on the transducer head.
10. Place transducer over spinous process at C4 level.
11. When ready, press “Freeze” and then “P1” to capture the image.
left side.
13. When ready, press “Freeze” and then “P1” to capture the image.
“Freeze” and then “P1”.
right side.
16. When ready, press “Freeze” and then “P1” to capture the image
“Freeze” and then “P1”.
18. To retrieve clips from live image screen:
a. Press “Freeze” button (lower right of control panel) so that it is lit
up.
437
b. Press unmarked button (lower left off centre of control panel). This
will make the cursor appear.
c. Move trackball to desired image.
d. Press “Set /B Pause” button (lower right off centre of control
panel).
19. To retrieve clips from home screen:
a. Press “New Patient” (left side of control panel).
b. Choose the participant name or ID of interest from the list at the
bottom of the screen.
c. Press “Set /B Pause” button (lower right off centre of control
panel).
d. Move trackball to “Image History” on upper left of screen. Press
“Set /B Pause” button to select image.
20. To measure:
a. Press “Measure” button above trackball.
b. Move the trackball to position the active caliper at the point of
interest.
c. Press “Set /B Pause” button to fix caliper at start point.
d. Move the trackball along the distance or depth.
e. Press “Set /B Pause” button to fix first caliper at end point.
21. To save image on hard disk:
a. Press unmarked button (lower left off centre of control panel). This
will make the cursor appear.
b. Move cursor using trackball to image of interest then click “Set /B
Pause” button.
c. Move trackball to Menu on right bottom corner of screen then click
“Set /B Pause” button.
d. Select “Save as”.
e. In “Save in” box, choose “HD (E:\export)” from dropdown
choices.
f. Write file name as “(Participant ID_left/right_resting/contracting”)
e.g. IS-000_left_resting
g. Use the following parameters for the rest of the details:
i. Image only
ii. Compression: None
iii. Quality: 100
iv. Save as type: Jpeg (*.jpg)
22. To save image on removable disk:
a. Plug in removable disk (USB port at the back)
b. Follow instructions for saving to hard disk but choose to save in
removal disk.
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5.3 Classification to Headache Groups
5.3.1 Checklist for Migraine Group
ICHD-3 beta criteria 2.3.1. Migraine without Participant response

aura
A. At least 5 attacks fulfilling criteria B-D
B. Headache attacks lasting 4-72 hours (untreated
or unsuccessfully treated)
C. Headache has at least two of the following
characteristics:
 Unilateral location
 Pulsating quality
 Moderate or severe pain intensity
 Aggravation by or causing avoidance of
routine physical activity (eg walking or
climbing stairs)
D. During headache at least one of the following
 Photophobia
 Phonophobia
E. Not better accounted for by another ICHD-3
diagnosis
ICHD-3 beta criteria 2.3.2. Migraine with Participant response

aura
A. At least 2 attacks fulfilling criteria B and
C
B. One or more of the following fully
reversible aura symptoms:
 Visual (e.g. flickering lights, spots or
lines, loss of vision)
 Sensory (e.g. pins and needles,
numbness)
 Speech and/or language
 Motor
 Brainstem
 Retinal
C. At least two of the following:
 At least one aura symptom develops
gradually over > 5minutes, and/or two
or more symptoms occur in
succession
439
ICHD-3 beta criteria 2.3.2. Migraine with Participant response
aura
 Each individual aura symptom lasts 5-
60 minutes
 At least one aura symptom is
unilateral
 The aura is accompanied, or followed
within 60 minutes, by headache
D. Not better accounted for by another
ICHD-3 diagnosis, and transient
ischaemic attack has been excluded
ICHD-3 beta criteria 2.3.3. Chronic Participant response

migraine
A. Headache (tension-type like and/or
migraine-like) on > 15 days per
month for > 3 months and fulfilling
criteria B and C
B. At least 5 attacks fulfilling criteria
B-D for migraine without aura
and/or criteria B and C for migraine
with aura
C. Headache attacks lasting 4-72
hours (untreated or unsuccessfully
treated)
D. Headache has at least two of the
following characteristics:
 Unilateral location
 Pulsating quality
 Moderate or severe pain
intensity
 Aggravation by or causing
avoidance of routine physical
activity (eg walking or climbing
stairs)
E. During headache at least one of the
following
 Photophobia
 Phonophobia
F. One or more of the following fully
440
ICHD-3 beta criteria 2.3.3. Chronic Participant response
migraine
reversible aura symptoms:
 Visual (e.g. flickering lights,
spots or lines, loss of vision)
 Sensory (e.g. pins and needles,
numbness)
 Speech and/or language
 Motor
 Brainstem
 Retinal
G. At least two of the following:
 At least one aura symptom
develops gradually over >
5minutes, and/or two or more
symptoms occur in succession
 Each individual aura symptom
lasts 5-60 minutes
 At least one aura symptom is
unilateral
 The aura is accompanied, or
followed within 60 minutes, by
headache
H. On > 8 days per month for > 3
months, fulfilling any of the
following:
 Criteria C and D for migraine
without aura
 Criteria B and C for migraine
with aura
 Believed by the participant to
be migraine at onset and
relieved by a triptan or ergot
derivative
I. Not better accounted for by another
ICHD-3 diagnosis
Fulfilled criteria for migraine?

 Yes: Included in Migraine Group
 No: Consider inclusion in Other Non-Migrainous Headaches Group
441
5.3.2 Checklist for Other Non-Migrainous Headaches Group
5.3.2.1 Tension-type headache
ICHD-3 beta criteria 2.4.1.1. Infrequent episodic Participant response

tension-type headache
A. At least 10 episodes of headache occurring on <1
day per month on average (<12 days per year)
and fulfilling criteria B-D
B. Lasting from 30 minutes to 7 days
 Bilateral location
 Pressing or tightening (non-pulsating) quality
 Mild or moderate intensity
 Not aggravated by routine physical activity
such as walking or climbing stairs
D. Both of the following:
 No nausea or vomiting
 No more than one of photophobia or
phonophobia
diagnosis
ICHD-3 beta criteria 2.4.1.2. Frequent Participant response

chronic tension-type headache
A. At least 10 episodes of headache occurring
on 1-14 days per month on average for > 30
months (> 12 days and < 180 days per year)
and fulfilling criteria B-D
B. Lasting from 30 minutes to 7 days
 Pressing or tightening (non-pulsating)
quality
 Not aggravated by routine physical
activity such as walking or climbing
stairs
 No nausea or vomiting
 No more than one of photophobia or
phonophobia
diagnosis
442
ICHD-3 beta criteria 2.4.1.3. Chronic Participant response
tension-type headache
A. > 15 days per month on average for >3
months (> 180 days per year),
fulfilling criteria B-D
B. Lasting hours to days or unremitting
 Pressing or tightening (non-
pulsating) quality
 Not aggravated by routine physical
activity such as walking or
climbing stairs
 No more than one of photophobia,
phonophobia or mild nausea
 Neither moderate or severe nausea
or vomiting
E. Not better accounted for by another
ICHD-3 diagnosis
5.3.2.2 Cervicogenic headache
ICHD-3 beta criteria 2.4.2. Cervicogenic Participant response

headache
A. Any headache fulfilling criterion C
B. Clinical, laboratory and/or imaging
evidence of a disorder or lesion within the
cervical spine or soft tissues of the neck,
known to be able to cause headache
C. Evidence of causation demonstrated by at
least two of the following:
 Headache has developed in temporal
relation to the onset of the cervical
disorder or appearance of the lesion
 Headache has significantly improved or
resolved in parallel with improvement
in or resolution of the cervical disorder
or lesion
 Cervical range of motion is reduced and
headache is made significantly worse by
provocative manoeuvres
 Headache is abolished following
443
ICHD-3 beta criteria 2.4.2. Cervicogenic Participant response
headache
diagnostic blockade of a cervical
structure or its nerve supply
D. Not better accounted for by another ICHD-3
diagnosis
 Yes: Included in Other Non-Migrainous Headaches Group

 No: Consider inclusion as mixed type or unclassifiable
444
6.0 REDCap headache diary for 6 months
7.0 Follow up at 1 month, 3 months and 6 months after enrolment

7.1 REDCap headache diary
7.2 McGill Pain Questionnaire
7.3 Central Sensitization Inventory
7.4 Headache Impact Test-6
7.5 The Henry Ford Headache Disability Index
7.6 Headache Disability Questionnaire
7.7 WHO Disability Assessment Schedule 2.0
445
APPENDIX 6
Summary of Media Coverage for the Study
Presented in Chapter 3
This summary was provided by The University of Sydney Media Office.
446
WED 17 FEBRUARY 2016
Media coverage on migraine and GABA study
Executive summary
The following is a summary of the media coverage gained on the study 'Elevated levels of GABA+ in migraine detected using 1HMRS'
NMR in Biomedicine, May 2015.
The study was released to the media in October 2015 with Maria Aguila as the media spokesperon.
The media coverage gained reached an estimated audience of 2,028,208, with the biggest audience share from TV.
*Note: This report may not capture all online articles.
A cure for debilitating migraines could be a step closer thanks to a world-first ...
Channel 7, Perth, Seven News, Rick Ardon and Susannah Carr 13 Oct 2015 6:20 PM
Duration: 1 min 32 secs • ASR AUD 14,523 • WA • Australia • Radio & TV • ID: M00063542601
A cure for debilitating migraines could be a step closer thanks to a world-first breakthrough by
University of Sydney researchers. They've discovered a chemical imbalance of a substance
called GABA in the brain of sufferers, and are now looking to develop new ways to treat the
condition.
Audience
191,000 ALL, 80,000 MALE 16+, 94,000 FEMALE 16+
Interviewees
Maria Aguila, University of Sydney|Marnee McKay, Migraine Sufferer
Also broadcast from the following 1 station
GWN7 (Perth)
COPYRIGHT This report and its contents are for the internal research use of Mediaportal subscribers only and must not
be provided to any third party by any means for any purpose without the express permission of Isentia and/or the relevant
copyright owner. For more information contact [email protected]
447
DISCLAIMER Isentia makes no representations and, to the extent permitted by law, excludes all warranties in relation to
the information contained in the report and is not liable for any losses, costs or expenses, resulting from any use or misuse
of the report.
A cure for migraine could be one step closer thanks to a breakthrough by researchers at ...
Channel 7, Melbourne, Seven News, Jennifer Keyte 13 Oct 2015 6:28 PM
Duration: 2 mins 0 sec • ASR AUD 50,286 • VIC • Australia • Radio & TV • ID: M00063540742
A cure for migraine could be one step closer thanks to a breakthrough by researchers at the
University of Sydney.
Audience
327,000 ALL, 128,000 MALE 16+, 179,000 FEMALE 16+
Interviewees
Also broadcast from the following 9 stations
Prime7 Albury (Albury), Prime7 Ballarat (Ballarat), Prime7 Bendigo (Bendigo), Prime7 Gippsland (Sale), Prime7
Mildura (Mildura), Prime7 Shepparton (Shepparton), Prime7 Swan Hill (Swan Hill), Prime7 Warrnambool
(Warrnambool), Southern Cross Darwin (Darwin)
A cure for debilitating migraines could be a step closer thanks to a world-first ...
Channel 7, Brisbane, Seven News, Sharyn Ghidella and Bill McDonald 13 Oct 2015 6:30 PM
Duration: 1 min 51 secs • ASR AUD 37,070 • QLD • Australia • Radio & TV • ID: M00063541425
A cure for debilitating migraines could be a step closer thanks to a world-first breakthrough by
University of Sydney researchers. They've discovered a chemical imbalance of a substance
called GABA in the brain of sufferers, and are now looking to develop new ways to treat the
condition.
Audience
405,000 ALL, 133,000 MALE 16+, 224,000 FEMALE 16+
Interviewees
Seven Bundaberg (Bundaberg), Seven Cairns (Cairns), Seven Central (Alice Springs), Seven Mackay (Mackay),
Seven Mt Isa (Mt Isa), Seven Rockhampton (Rockhampton), Seven Sunshine Coast (Sunshine Coast), Seven
Toowoomba (Toowoomba), Seven Townsville (Townsville)
COPYRIGHT For the internal research use of Mediaportal subscribers only. Not to be provided to any third party for any purpose without the express
permission of Isentia. For further information contact [email protected]
448
Research at the University of Sydney into migraines has found a chemical called Gamma ...
Channel 7, Sydney, Seven News, Mark Fergusson 13 Oct 2015 6:47 PM
Duration: 2 mins 0 sec • ASR AUD 87,548 • NSW • Australia • Radio & TV • ID: M00063541157
Research at the University of Sydney into migraines has found a chemical called Gamma which
causes them. Migraines cost the economy $7b a year.
Audience
406,000 ALL, 133,000 MALE 16+, 232,000 FEMALE 16+
Interviewees
Prime7 ACT (Canberra), Prime7 Armidale (Armidale), Prime7 Coffs Harbour (Coffs Harbour), Prime7 Cooma
(Cooma), Prime7 Dubbo (Dubbo), Prime7 Gold Coast (Gold Coast), Prime7 Griffith (Griffith), Prime7 Moree
(Moree), Prime7 Newcastle (Newcastle), Prime7 North Coast (Lismore), Prime7 Orange (Orange), Prime7
Tamworth (Tamworth), Prime7 Taree (Manning River), Prime7 Wagga Wagga (Wagga Wagga), Prime7
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Migraine breakthrough: One step closer to solving the painful puzzle

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Chemical imbalance linked to migraines

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What I Live With: The Untold Toll Of Migraines Experienced By 1 In 10 Australians
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Headache over for migraine researchers?

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Brain is linked to the pain
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FED:CheckUp medicaL column for October 16

A weekly round-up of news affecting your health
By Margaret Scheikowski and Angelo Risso
WALK UNNATURALLY TO BURN MORE KILOJOULES
If you want to burn more kilojoules when you're walking, just do "weird" things.
That's the advice of the co-author of an engineering study which found that varying your walking speed
can burn up more energy than maintaining a steady pace.
The very act of changing speeds burns energy, says Professor Manoj Srinivasan from The Ohio State
University.
"Walking at any speed costs some energy but when you're changing the speed, you're pressing the gas
pedal, so to speak.
"Changing the kinetic energy of the person requires more work from the legs and that process certainly
burns more energy."
Other ways for walkers to burn more kilojoules involve doing it in a way that feels unnatural.
"Just do weird things," he says.
"Walk with a backpack, walk with weights on your legs. Walk for a while, then stop and repeat that.
"Walk in a curve as opposed to a straight line."
SLEEPY DRIVERS AS DANGEROUS AS DRUNK ONES
Tired? Behind the wheel? You might as well be drink-driving.
A Queensland University of Technology study found young drivers were more likely to drive drowsy than
drunk, despite the act being equally as dangerous.
The study examined 114 drivers under 30 and 177 drivers over 30, finding young drivers were both more
likely to 'sleepy drive' and to disapprove of enforcement practices for sleepy driving.
"What this shows is that drivers, in particular young drivers, don't view equally the dangers of drink
driving and sleepy driving despite the crash risks being similar," researcher Chris Watling said.
"Given younger drivers are over-represented in crash statistics and more likely to be impaired by
sleepiness, it is vital we look to increase their perception of the dangers of driving while sleepy."
Research shows a blood alcohol content of 0.05 is the same as 17 consecutive hours awake, while 20
hours awake is the equivalent of a 0.1.
NDIS GUIDE FOR MENTAL HEALTH CARERS
Navigating Australia's new National Disability Insurance Scheme isn't easy.
But people who provide unpaid care and support to a family member or friend with a psychosocial
disability related to a mental condition can now be helped by a new guide.
Psychosocial disability describes the experience of people with impairments and participation restrictions
related to mental health conditions.
The guide, developed by Mental Health Australia and Carers Australia, can be accessed at
http://mhaustralia.org/ and http://www.carersaustralia.com.au/
HEADACHE OVER FOR MIGRAINE RESEARCHERS?
Migraines have been puzzled over for years but the code may finally have been cracked.
University of Sydney researchers have found higher levels of the gamma-aminobutyric acid (GABA)
chemical are present in the brains of migraine sufferers.
GABA is the brain's most abundant inhibitory brain chemical and plays a major role in a person's pain
threshold.
This lends support to the idea migraines are caused by chemical imbalances in the brain.
"For such a debilitating condition, very little is known about migraine so this is a big step forward and
could lead to better diagnosis and treatment of the disease in the future," lead researcher Maria Aguila
said.
"GABA could be used to help us identify migraine sufferers and track responses to drug trials and
measuring GABA levels over a period of time could well reveal what's causing attacks."
GROW MEDICINES IN YOUR BACKYARD?
Two scientists seeking to re-engineer plant proteins to tackle diabetes, obesity and cancer could be a
step closer to their goal.
David Craik from the University of Queensland and Marilyn Anderson from La Trobe University have
taken out the prestigious $1 million Ramaciotti Biomedical Research Award to produce "next generation"
biodrugs incorporated into plant products such as seeds and teas.
This could enable patients to cheaply grow medicines in their own backyard, saving millions of lives
across the developing world.
"This type of blue-sky research falls outside the realm of work typically funded by government or industry
so we are particularly grateful," Professor Craik said.
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Researching the
baffling migraine
Migraines have baffled scientists for years - study fundamental changes in brain chem-
no-one knows why they come or how they go istry that are associated with migraine, but
- but researchers at the University of Sydney they also open a whole new world with
have taken a significant step forward in respect to monitoring a patient's response to
understanding the debilitating condition. treatment and compliance," he said.
A new study, reveals higher levels of the The researchers were unable to tell if the
chemical gamma-aminobutyric acid in the increase in GABA is related to a recent
brain of migraine sufferers, supporting the migraine attack or signalling a new one as the
theory that migraines are linked to a chemical scanning process is currently too complex to
imbalance in the brain. carry out during a migraine attack.
"The finding paves the way for the dis- Fast facts on migraine -
covery of new, effective treatments for
migraines," said lead researcher Maria z Migraine is the third most com-
Aguila, PhD candidate in the Faculty of mon disease in the world;
Health Sciences.
z It is estimated to affect 1 in 7
"For such a debilitating condition, very adults;
little is known about migraine so this is a big
step forward and could lead to better diagno- z It is up to three times more com-
sis and treatment of the disease in the future," mon in women than men;
she said.
z Often starting at puberty,
Gamma-aminobutyric acid or GABA as it migraine most affects those
is commonly known, is the most abundant aged between 35 and 45 years;
inhibitory brain chemical and has long been
suspected to play a role in migraines because z Current diagnosis is based on a
of its ability to influence pain. This study is complex checklist of signs and
the first to accurately measure GABA levels symptoms, and;
in the living brain.
z Migraine is believed to be under-
While the expert are still at a loss to reported and under diagnosed
understand "what causes migraine, how it globally.
starts and ends, or why the triggers appear to
differ from one person to the next" the latest
finding can assist with more specific
research, Ms Aguila said.
"For example, GABA could be used to
help us identify migraine sufferers and track
responses to drug trials, and measuring
GABA levels over a period of time could
well reveal what's causing attacks."
The study compared the levels of GABA
in twenty chronic migraine sufferers to an
age and gender matched control group who
did not experience any form of regular
headaches. Brain scans were conducted when
the participants were not having a migraine.
Associate Professor in Neuroimaging,
Jim Lagopoulos said the ability to directly
measure these chemicals in the brain would
not have been possible several years ago.
"These advances not only allow us to
d f d l h i b i h
454
26 Oct 2015
Newcastle Herald, Newcastle NSW
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Headache over for migraine researchers?

MIGRAINES have been puzzled over for years but the
code may finally have been cracked. University of Sydney
researchers have found higher levels of the gamma-
aminobutyric acid (GABA) chemical in the brains of
migraine sufferers. GABA is the brain’s most abundant
inhibitory brain chemical and plays a major role in a
person’s pain threshold. This lends support to the idea that
migraines are caused by chemical imbalances in the brain.
The finding could lead to better diagnosis and treatment.
‘‘GABA could be used to help us identify migraine sufferers
and track responses to drug trials and measuring GABA
levels over a period of time could well reveal what’s
causing attacks,’’ lead researcher Maria Aguila said.
455
31 Oct 2015
Western Advocate, Bathurst NSW
Author: Margaret Scheikowski • Section: General News • Article type : News Item
Classification : Regional • Audience : 2,707 • Page: 13 • Printed Size: 264.00cm²
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back
Headache may be over for migraine researchers

Checkup But people who provide unpaid care
and support to a family member or friend
Margaret Scheikowski with a psychosocial disability related to a
mental condition can now be helped by a
M
IGRAINES have been puzzled over new guide.
for years but the code may finally Psychosocial disability describes the
have been cracked. experience of people with impairments
University of Sydney researchers have and participation restrictions related to
found higher levels of the gamma- mental health conditions.
aminobutyric acid (GABA) chemical are The guide, developed by Mental Health
present in the brains of migraine sufferers. Australia and Carers Australia, can be
GABA is the brain’s most abundant accessed at http://mhaustralia.org/ and
inhibitory brain chemical and plays a http://www.carersaustralia.com.au/
major role in a person’s pain threshold. ■■■
This lends support to the idea migraines LOGIE-WINNING actor John Wood is
are caused by chemical imbalances in the fronting a new campaign to raise aware-
brain. ness about shingles, which will affect one
“For such a debilitating condition, very in three adults.
little is known about migraine, so this is a The condition, involving the painful
big step forward and could lead to better outbreak of rash or blisters, is estimated to
diagnosis and treatment of the disease in have doubled among the over-60s in
the future,” lead researcher Maria Aguila recent years, says Chronic Pain Australia.
said. Half will go on to experience longer-
“GABA could be used to help us identify term nerve pain, lasting 3.5 years on aver-
migraine sufferers and track responses to age.
drug trials and measuring GABA levels Wood was bedridden for 13 weeks when
over a period of time could well reveal
what’s causing attacks.” he first had shingles as a teenager and had
■■■ it again while filming Blue Heelers in his
TWO scientists seeking to re-engineer 50s.
“I want to make sure that those at high-
plant proteins to tackle diabetes, obesity est risk, people over 60, know about the
and cancer could be a step closer to their potential pain and suffering that shingles
goal. can cause and have a conversation with
David Craik from the University of their doctor about their risk,” he said.
Queensland and Marilyn Anderson from ■■■
La Trobe University have taken out the SHINGLES often has vague symptoms
prestigious $1 million Ramaciotti such as mild to severe pain in a particular
Biomedical Research Award to produce area, or a rash, leading people to dismiss
“next generation” biodrugs incorporated the possibility until it’s too late to treat the
into plant products such as seeds and teas. nerve damage.
This could enable patients to cheaply People with gut problems are taking
grow medicines in their own backyard, part in a world-first trial of an Australian
saving millions of lives across the develop- seaweed extract.
ing world. University of Wollongong researchers
“This type of blue-sky research falls out- are investigating whether the extract can
side the realm of work typically funded by help prevent the onset of chronic disorders
government or industry so we are particu- such as Type 2 Diabetes.
larly grateful,” Professor Craik said. Seaweed dietary fibres are known to
■■■ improve the gut and digestive condition of
NAVIGATING Australia’s new National animals and reduce metabolic stress such
Disability Insurance Scheme isn’t easy. as experienced in the pre-diabetic condi-
tion.
456
03 Nov 2015
Inner West Courier, Sydney
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CAMPERDOWN
Brain is linked to the pain

MIGRAINE STUDY’S FINDINGS
IT’S A disease that has baf-
fled health professionals for and track responses to drug
years, but University of Syd- trials, and measuring GABA
ney research has findings levels over a period of time
that support the theory that could well reveal what’s
migraines are linked to a causing attacks.”
chemical imbalance in the The study compared the
brain. levels of GABA in 20 chronic
A new study reveals high- migraine sufferers to an age-
er levels of the chemical and gender-matched control
gamma-aminobutyric acid group who did not experi-
in the brain of migraine suf- ence any form of regular
ferers and paves the way for headache.
the discovery of new, effec- Brain scans were conduc-
tive treatments, said lead re- ted when the participants
searcher Maria Aguila, PhD were not having a migraine.
candidate in the Faculty of The researchers were un-
Health Sciences. able to tell if the increase in
“For such a debilitating GABA is related to a recent
condition, very little is migraine attack or signal-
known about migraine so ling a new one, as the scan-
this is a big step forward and ning process is currently too
could lead to better diag- complex to carry out during
nosis and treatment of the a migraine attack.
disease in the future.”
Gamma-aminobutyric ONE IN SEVEN HIT
acid, or GABA as it is com- Migraine is the third most University of Sydney researchers believe that migraines may
monly known, has long been common disease in the world be linked to a chemical imbalance in the brain.
suspected to play a role in It is estimated to affect one
migraines due to its ability in seven adults
to influence pain. It is up to three times more
“We still don’t know what common in women than men
causes migraine, how it Often starting at puberty,
starts and ends … but this migraine most affects those
aged between 35 and 45
discovery means that we can
Current diagnosis is based
now be much more specific
on a complex checklist of
with our research going for- signs and symptoms
ward,” said Ms Aguila. Migraine is believed to be
“For example, GABA under-reported and under
could be used to help us diagnosed globally
identify migraine sufferers
457
APPENDIX 7
Cover Art Published in Journal of Pain
Appendix 7 presents the cover art published in The Journal of Pain Volume 17, Issue 10
(October 2016) (http://www.jpain.org/issue/S1526-5900(16)X0011-9). The cover illustration
was a stylised image from an output of the editing process of GABA from the study in
Chapter Four published in the same issue: [Aguila ME, Rebbeck T, Leaver AM, Lagopoulos
J, Brennan PC, HübscherM,Refshauge KM. The association between clinical characteristics
of migraine and brain GABA levels: An exploratory study. J Pain 2016; 17:1058–67.
doi:10.1016/j.jpain.2016.06.008]
458
459
460
APPENDIX 8
The Clinical Significance of Immediate Symptom Responses to
Manual Therapy Treatment for Neck Pain:
Observational Secondary Data Analysis of a Randomized Trial
Appendix 8 is the peer reviewed version of the following article: Trott, CA, Aguila, MER,
Leaver, AM, The clinical significance of immediate symptom responses to manual therapy
treatment for neck pain: Observational secondary data analysis of a randomized trial. Man
Ther. 2014; 19:549–554.doi: 10.1016/j.math.2014.05.011, which has been published in final
form athttp://www.mskscienceandpractice.com/article/S1356-689X(14)00113-1/fulltext; with
permission from Elsevier.
461
As co-authors ofthe paper “The clinical significance of immediate symptom responses to
manual therapy treatment for neck pain: Observational secondary data analysis of a
randomized trial”, we confirm that Maria Eliza Ruiz Aguila has madethe following
contributions:
Signed: Caelum A Trott Date: 31 March 2017
462
The clinical significance of immediate symptom responses to manual therapy
treatment for neck pain: an observational study
Caelum A Trott1BAppSc(PhtyHon); Maria Eliza Ruiz Aguila1,2MPhysio, BSPT,

BSBio; Andrew M Leaver1 PhD, BAppSc(Phty), GDipAppSc(ManipPhty)
1
Faculty of Health Sciences, The University of Sydney, 75 East Street, Lidcombe
NSW 2141 Australia.
2
College of Allied Medical Professions, University of the Philippines, Pedro Gil
Street, Manila 1004 Philippines.
Current Appointments
Trott: Physiotherapist, Prince of Wales Hospital, Barker St, Randwick NSW 2031
Aguila: PhD candidate, Faculty of Health Sciences, The University of Sydney
Leaver: Lecturer, Faculty of Health Sciences, The University of Sydney
Dr Andrew Leaver,
75 East Street
Lidcombe NSW, 2141, Australia.
Tel: +61 2 9351 9545

Fax: +61 2 9036 7303
E: [email protected]
Word Count: 251 words (Abstract)

3685 words (Introduction, Method, Results, Discussion)
References: 27
Tables: 2
Figures: 1
463
ABSTRACT
Objective
Toexplore aspects of symptom responses to manual therapy treatment for neck pain.
Methods
An observational study based on data collected in a randomized trial.181 participants
seeking care from a physiotherapist or chiropractor for a new episode of neck pain
were included. Outcome variables included recovery timeand participant-perceived
effect of treatment (GPE) at 3-months.
Results
There was a significant reduction of ≥1.4points (95%CI 1.2 to 1.5) in pre- and post-
treatment pain scores at each occasion of treatment. There was also small but
significant increases in pain of ≤0.7points (95%CI 0.4 to 1.0) between each treatment
session, without regression to the preceding pre-treatment level. The relationships
between immediate post-treatment effects and longer-term outcomes were explored
using multivariate regression analyses. There was significant univariate association
between recovery time and cumulative post-treatment changes in pain from the
second, third and fourth (Exp(B)=1.2) treatment sessions, as well as the presence of
post-treatment headache (Exp(B)=0.7) and other minor adverse symptoms
(Exp(B)=0.6). There was significant univariate association between GPE at 3-months
and cumulative pain responses from first (B=0.2), second (B=0.3), third (B=0.3) and
fourth (B=0.4) treatment sessions. The change in pain after session 1 was
independently associated with GPE (B=0.2). There was a consistently significant
464
difference of ≥0.7points (95%CI 0.43 to 0.89) in the different methods of reporting
pain.
Conclusions
Our results show that manual therapy for neck pain involves a “two-steps forward,
one-step back” recovery pattern. Whilst minor adverse events are undesirable, they do
not seem to be significantly associated with long-term recovery.
KEY WORDS
Manual Therapy, Neck Pain, Manipulation Spinal, Pain Measurement
465
INTRODUCTION
Neck pain is a common musculoskeletal condition experienced by up to 15% of
people at any given time, and afflicting most people at some stage of their lives
(Haldeman et al., 2008; Hoy et al., 2010). Manual therapy is one of the few effective
treatments for neck pain, with demonstrated benefits in improving pain and function,
at least in the short term (Korthals-de Bos et al., 2003; Hurwitz et al., 2008; Driessen
et al., 2012). The clinical course of neck pain appears to have fluctuating periods of
aggravation and remission, with recurrence a common feature of the condition (Cote
et al., 2004; Haldeman et al., 2008; Hush et al., 2011). Based on current evidence, it
would appear that manual therapy is of most value in reducing symptoms, restoring
function and hastening recovery during an episode of acute neck pain.
Although acknowledged as an effective treatment, the therapeutic mechanisms
underpinning manual therapy are not fully understood, and many different theoretical
and philosophical approaches exist amongst and between the disciplines that practice
manual therapy. One of the most widely recognized approaches to manual therapy
practice is the approach developed by Australian physiotherapist Geoffrey Maitland.
One of the key features of Maitland’s approach was the emphasis on monitoring and
reassessing symptoms during and after application of a technique, as a means guiding
choice of technique, dosage and treatment progression (Maitland, 1970; Maitland,
1986). This approach differed from the approaches of many of Maitland’s
contemporaries who tended to focus more on biomechanical principles to guide
treatment decisions (Larson, 2005).
466
The use of patient-reported numerical ratings of current pain intensity to guide
treatment selection and to monitor treatment outcomes is now widespread in modern
manual therapy practice. Numerical rating scales for pain are also widely used as
primary outcome measures in clinical trials of manual therapy, as a means of
determining recovery from an episode of neck pain.The construct of recovery,
howver, is complex and multidimensional, encompassing many different elements
that are not necessarily captured by a single number. Focus group interviews of
people with back pain for example, have shown that people with pain scores of zero
do not necessarily consider themselves recovered, and some who consider themselves
recovered can still register pain scores above zero (Hush et al., 2009).Inconsistencies
have been demonstrated between verbal reports of pain and the standardized
questionnaires that measure pain and disability in people with low back pain (Ong et
al., 2006; De Souza and Frank, 2007).Better understanding of the relationship
between pain scores and patient-relevant indices of recovery, and the ability to
identify possible biases in patient reports of sympotms might improve monitoring of
clinical and research outcomes in people with neck pain.
Several studies have previously investigated the relevance of within-session changes
in symptoms in patients undergoing manual therapy treatment. There is some
evidence that symptom changes that occur within a treatment session are maintained
between treatment sessions (Hahne et al., 2004; Tuttle, 2005; Tuttle et al., 2006;
Tuttle, 2009), and tend to continue throughout the duration of care (Cook et al., 2012).
There is also some evidence to suggest that changes in pain and disability scores
during treatment correlate with self-reported rate of recovery(O’Halloran et al., 2013).
This suggests a relationship between positive treatment responses and recovery in the
467
very short term. The relationship between positive within-session treatment responses
and longer-term recovery, however, is lacking. Further, the previous studies into the
within- session responses to manual therapy concentrated primarily on the positive
effects of manual therapy, such as improvement in pain and range of motion. Manual
therapy can also result in a range of minor adverse effects (Hurwitz et al., 2005) most
commonly increased neck pain and headache. Less is known about the effect of these
adverse effects on recovery.
The aim of this study was to explore aspects of the immediate symptom responses to
manual therapy treatment, in people with neck pain. Specifically, this study aimed to
investigate
1. The typical clinical course of reported symptoms during a short episode of
manual therapy care
2. The relationship between the immediate changes in reported pain following
manual therapy and longer-term outcomes
3. The influence of minor adverse effects of manual therapy on longer-term
outcomes
4. The consistency between pain scores reported by patients to practitioners and
those recorded by patients in diaries.
468
METHODS
Design
This study involved observational secondary data analysis from a randomized
controlled trial (Leaver et al., 2010) that compared high-velocity thrust manipulation
with non-thrust mobilization in people with a new episode of neck pain. The original
randomized controlled trial demonstrated no difference in outcomes between the
manipulation and mobilization groups. We were therefore able to combine both
treatment groups for an observation study.
Participants in the randomized controlled trial kept a daily diary of pain scores and the
participating practitioners recorded pre- and post-treatment pain scores at each
treatment session. This provided an opportunity to explore the relationship between
the short-term effects of manual therapy treatments and longer-term patient relevant
outcomes, as well as other features of manual therapy care. The study was approved
by the University of Sydney Human Research Ethics Committee and all participants
provided written informed consent.
Participants
The study was conducted in 11 physiotherapy and chiropractic clinics in Sydney,
Australia, between October 2006 and April 2008. Participants aged 18-70 years who
were seeking care from a physiotherapist or chiropractor for a new episode of non-
specific neck pain were recruited by their treating practitioner. Eligible participants
had neck pain of less than three months duration that was preceded by at least one
month without neck pain. Participants were excluded if they had whiplash-associated
disorder, history of neck surgery, serious pathology (e.g. malignancy, infection,
inflammatory disorder, fracture, radiculopathy or myelopathy), primary complaint
469
other than neck pain, mild neck pain (<2/10 on a 0-10 point scale) or were unable to
communicate in English. For the purpose of the associated randomized controlled
trial, participants were also excluded if the treating practitioner deemed them
unsuitable for neck manipulation. Participants from both groups (i.e. manipulation
and mobilization) were included in the observational study.
Procedures
Baseline data were collected using participant questionnaires and practitioner
assessment forms (Leaver et al., 2010). All participants were treated with up to four
sessions of multimodal physical therapy that included manual therapy. The manual
therapy that was provided to participants was either high velocity thrust manipulation
or non-thrust mobilization according to the randomization schedule of the associated
randomized controlled trial. Participants were followed for a period of three months
after baseline assessment. The manual therapy treatments were applied pragmatically
with the treating manual therapists selecting the target spinal segment, manual therapy
technique and grade according to their clinical judgment. The treating practitioners
were physiotherapists and chiropractors with post-graduate training and qualifications
in spinal manipulative therapy, with at least two years of post-graduate experience.
Participants completed a pain diary for three months. Diary entries were collected by
telephone and transcribed weekly to minimize loss of data. An exit interview was
conducted by telephone at three months to obtain participant’s pain, activity and
global perceived effect scores. The sample size was determined by the original trial
and was powered to explore the differences between mobilization and manipulation in
terms of speed of recovery.
470
Variables/outcomes
Demographic variables collected at baseline included age, sex, smoking habit, self-
rated general health (5-point categorical scale) and compensation status. Clinical
variables collected at baseline included pain intensity (numerical rating scale 0-10),
duration of the current episode of neck pain in days, neck-related disability (Neck
Disability Index 0-50), past history of neck pain, use of analgesic medications and the
presence of associated symptoms including arm pain, headache, upper back pain,
lower back pain, dizziness and/or nausea.
Pre-treatment and immediate post-treatment pain scores were recorded by the treating
practitioner using a 0-10 numerical rating scale (NRS). ‘Within-session’ changes in
pain were calculated as the difference between pre-treatment and post-treatment
scores at each treatment session. ‘Cumulative change in pain’ relative to baseline was
also calculated as the difference between the baseline pain score and the post-
treatment score at each treatment session. Variables recorded in the participant diary
included average 24-hour pain scores on a daily basis for three months as well as
Neck Disability Index (NDI) (Vernon and Mior, 1991) and Global Perceived Effect
(GPE) (Kamper et al., 2010) at three-month follow-up. Adverse effects of treatment
were recorded in the participant diary during the treatment period. A checklist of
common minor adverse effects including additional neck pain, additional headache,
dizziness, nausea, fatigue and other was used as well as open-ended questioning.
The outcome variables were the recovery time for the episode of neck pain and the
participants’ perception of treatment effects. Recovery time for the episode of neck
pain was defined as the number of days it took from the day of enrolment in the study
for a participant to report a pain score of <1 (NRS 0-10) for the first of seven
471
consecutive days. The participants’ perception of the effects of treatment was
measured with the Global Perceived Effect scale (GPE). The GPE scale rates
perception of recovery on a scale from -5 (Much worse) to +5 (Much better) and is a
reliable and patient-focused indicator of recovery (Kamper et al., 2010).
Statistical analysis
All data were analyzed using Statistical Package for Social Sciences (SPSS)®
Baseline demographic and clinical characteristics were reported as frequencies (%) or
using descriptive statistics.The clinical course of neck pain during the two-week
episode of care was reported by plotting pre- and post-treatment pain scores for each
treatment session during the episode of care. Repeated measures t-test was used to
compare pre- and post-treatment scores within and between sessions.
The relationships between immediate positive and adverse post-treatment effects and
longer-term outcomes were explored using multivariate regression. Specifically, the
relationship between post-treatment effects and recovery time was explored using
Cox regression. The relationship between post-treatment effects and the perceived
effects of treatment at three-month follow-up was explored using linear regression.
For both regression models, the univariate relationships between the within-session
changes in pain (including the cumulative changes in pain scores from baseline at
each treatment session) and adverse events were calculated. In the multivariate
analysis, all variables associated (p<0.1) with faster recovery or better-perceived
treatment outcomes were included in the regression models. Variables that no longer
472
associated with recovery were removed in a stepwise manner. Where there was strong
correlation (Pearson r>0.4) between the predictor variables, the earliest associated
post-treatment response and the adverse effect with the strongest association were
included in the multivariate model. Clinical and demographic variables, previously
shown (Leaver et al., 2013) to be associated with either faster recovery (better self-
rated general health, shorter duration of symptoms, being a smoker, and absence of
concomitant upper back pain or headache) or higher disability (concomitant upper or
lower back pain, older age, and previous sick leave for neck pain) were also included
in the multivariate models. Data and residuals were explored to ensure that all
assumptions for the use of linear regression analysis were met (Zuur et al., 2010).
The consistency between post-treatment pain scores recorded by the treating therapist
and those recorded by the patients in their diaries 24-hours after a treatment session
was tested using paired-samples t-tests.
RESULTS
Participant characteristics
One hundred and eighty-one participants were recruited. Of the 237 patients screened,
56 were excluded due to either not meeting the eligibility criteria (n = 46) or declining
to participate (n = 10). Five participants withdrew from the study before the three-
month follow-up point. These participants were included in the survival analysis and
were censored at the date of last data collection. Two of the participants who were
lost to follow-up completed their course of treatment and were included in all
analyses that were related to the two-week treatment period. Three participants
withdrew from the study without completing the course of treatment and were
473
excluded from all analyses. Baseline participant characteristics are presented in Table
1. The cohort had an average age of 39 years, with two-thirds of participants being
female. Participants had moderate neck pain (NRS 6.2), moderate disability (NDI
16/50) and were seeking treatment on average three weeks into the episode of neck
pain. Concomitant symptoms occurred frequently, particularly pain affecting the
upper limb (79.6%), head (64.6%) and upper back (63.5%).
Clinical course of neck pain during a episode of manual therapy care
The clinical course of neck pain over the two-week treatment period, determined by
serial pre- and post-treatment pain scores featured a ‘descending saw-tooth’ pattern of
recovery (Figure 1). On each occasion of treatment there was a statistically significant
improvement in pain within the session, resulting in a trajectory of cumulative
improvement across the treatment period. There was also a consistent pattern of small
but statistically significant increases in neck pain between each treatment session.
These small relapses did not, on any occasion reach the level of the preceding pre-
treatment score.
Relationship between within session changes in symptoms and outcome
There was significant (p<0.1) univariate association between time taken to recover
from the episode of neck pain and several of the response to treatment variables
including; cumulative post-treatment change in pain from baseline after the second
(Exp (B)=1.2, 95% CI 1.1 to 1.3), third (Exp (B)=1.2, 95% CI 1.1 to 1.3) and fourth
(Exp (B)=1.2, 95% CI 1.1 to 1.4) treatment sessions, as well as post-treatment
headache (Exp (B)=0.7) and other minor adverse symptoms (Exp (B)=0.6). There
was moderate correlation between the cumulative post-treatment change in pain
474
scores from baseline at each of the treatment sessions (Pearson’s r 0.49, p<0.01). The
score from the earliest treatment session with univariate association, Session 2, was
included in the multivariate analysis. There was strong correlation between reports of
post-treatment headache and other minor adverse effects (Pearson’s r 1.0, p<0.01).
The presence of post-treatment headache was used in the multivariate analysis
because it had the strongest univariate association. None of the response to treatment
variables remained independently associated with recovery time after controlling for
duration of symptoms, self-rated general health, and baseline headache.
There was significant (p<0.1) univariate association between the perceived effects of
treatment at three months and cumulative post-treatment change in pain from baseline
after the first (B=0.2, 95% CI 0.0 to 0.4), second (B=0.3, 95% CI 0.1 to 0.4), third
(B=0.3, 95% CI 0.1 to 0.4) and fourth (B=0.4, 95% CI 0.2 to 0.5) treatment sessions.
The association between the perceived effects of treatment at three months and
reported adverse effects was not statistically significant. The earliest cumulative
change in post-treatment pain score with univariate association to GPE, Session 1,
was included in the multivariate analysis. The post-treatment change in pain from
Session 1 remained independently associated (B=0.2, 95% CI 0.01 to 0.4) with the
perceived effects of treatment at three months after controlling for concomitant upper
back pain, lower back pain, older age, and previous sick leave for neck pain.
Consistency of patient-reported pain scores
There was a significant difference (p<0.05) between the pain scores reported to the
treating practitioners and the scores recorded by participants in their diaries. On each
475
occasion of treatment, the average 24-hour pain scores recorded in the diaries was on
average approximately one point (0-10 NRS) higher than the scores reported to the
treating practitioner (Table 2).
DISCUSSION
A detailed investigation of the change in symptoms reported by patients and
practitioners in response to manual therapy for neck pain has provided clinically
relevant findings and has raised further clinical questions. These findings include new
information about the clinical course during an episode of manual therapy care, as
well as new information about the consistency between patient and practitioner
reports of changes in pain. This study also provides further confirmation of the value
of within-treatment changes in symptom levels and a means of predicting longer-term
outcomes.
Unlike previous studies that describe a rather pessimistic outlook for patients with
neck pain (Carroll et al., 2008; Hush et al., 2011), these results suggest that the
prognosis is quite favorable for those with a new episode of neck pain who are
identified by experienced manual therapists as suitable for manual treatments. These
participants experienced large and rapid improvement in neck symptoms over the
course of manual therapy treatment. The significant improvements in pain between
treatment sessions were consistent with previous research exploring manual therapy
in musculoskeletal pain (Cook et al., 2012), however by tracking changes in reported
symptoms from treatment to treatment rather than using strict time-contingent review
476
points, we also saw a pattern of recovery that would have otherwise not been evident.
There was a distinct pattern of a large improvement in reported pain scores within a
treatment session, followed by a slight relapse between sessions and this pattern was
consistent across the entire course of treatment. It is tempting to attribute the observed
pattern of recovery entirely to the beneficial effects of the treatment provided.
However our study did not include a no-treatment or placebo control and is therefore
limited in its ability to account for the non-specific interaction effects of the
treatment. A placebo-controlled trial with a similar review schedule would help to
identify whether natural recovery or regression to the mean play a role in the
identified pattern. Another limitation is the use of pain as the sole indicator of short-
term treatment success. The findings would have been strengthened by periodically
exploring other short-term outcomes measures like range of motion or function.
There is also reason for caution in interpreting the observed pattern of recovery due a
possible systematic bias in reporting of symptoms. The pain scores reported by
treating therapists were on average one point lower on the numerical rating scale than
scores independently recorded by patients over the following day. There are several
possible explanations for this finding. This discrepancy might represent the same
tendency for slight relapse following treatment suggested by the between-session
changes recorded by the practitioners. Alternatively, it is possible that patients under-
reported their post-treatment pain to the therapist out of a desire to please or seem
grateful. The use of blinded assessors for collection of pre- and post-treatment
outcomes might have yielded different results. It is also possible that the mode of
reporting, verbal versus written, has a systematic influence on the levels of pain
reported by the participants. Despite being a simple and apparently one-dimensional
477
scale, the relationship between a numeral rating of pain and perceptions of recovery is
complex (Hush et al., 2009). A qualitative research model could possibly be
employed to further explore some of the questions raised by our observations of the
difference in patient and therapists reports of pain.
Despite the differences in symptoms reported by the patients to the practitioners and
those recorded by the patients, both sets of pain scores demonstrated significant and
progressive improvements with each treatment session. This is important information
for patients who are being treated with manual therapy for neck pain. Evidence-based
guidelines for neck and low back pain and (van Tulder et al., 2006; Childs et al.,
2008) emphasize the importance of providing accurate and assuring information to
patients and setting expectations of recovery. For a patient, information that a brief
course of treatment is likely to be effective and that their recovery will probably
involve “two-steps forward, one-step back” is potentially helpful. Improving a
patient’s understanding of the context of a slight relapse between treatment sessions
might help provide additional reassurance and decrease negative affective
interpretations of relapses.
The other important finding for manual therapists and their patients was the
association between the immediate responses to manual therapy treatment and longer-
term outcomes. This is consistent with other studies that have demonstrated the
predictive value of within-session responses on treatment outcomes (Hahne et al.,
2004; Tuttle, 2005; Tuttle, 2009; O’Halloran et al., 2013), but adds information about
the broader value of treatment responses beyond the treatment period. There was an
independent association between within-session improvements in pain and the
478
perceived effects of treatment at three months after controlling for clinical and
demographic variables previously found (Leaver et al., 2013) to be associated with
neck-related disability. There was also a univariate association between the rate of
recovery and the cumulative improvement in pain scores at the second, third and
fourth treatment sessions. Whilst a progressive improvement in symptoms during a
course of treatment does not predict the rate of recovery independent of the duration
of pain, general health or absence of headache, it can still be a useful guide for
clinicians about expected progress. There is an intuitive link between short-term and
longer-term improvement, which can be incorporated into discussions with patients
about their expected course of recovery.
Minor adverse events such as headache during the treatment period are of course
undesirable, however our results suggest that the occurrence of such events does not
necessarily affect longer-term recovery. There was no independent association
between experiencing minor adverse events during the treatment period and recovery
time or the perceived effects of treatment at three months. A recent randomized
controlled trial(Walker et al., 2013) has shown that adverse events are common in
both manual therapy treatment groups and placebo controls, suggesting that these
events may be a feature of the condition rather than due to the effects of treatment.
The reporting of minor increases in pain or concomitant symptoms after manual
therapy might even relate to the tendency for minor regression of improvement
between treatments that our results demonstrate. This information can be used to
shape patients’ understanding that experiencing minor adverse events may be a part of
the recovery process and does not reflect impeded recovery.
479
Our results demonstrate than an episode of manual therapy care for patients with non-
specific neck pain results in rapid resolution of symptoms and a positive prognostic
outlook. By communicating the normality and relatively benign nature of minor
relapses and minor adverse events during treatment, therapists can assist in shaping
realistic patient expectations about recovery from the episode of neck pain. Although
discrepancies and imperfections exist in the reporting styles of pain, treatment
responses contain valuable information about longer-term outcomes and play a role in
predicting overall treatment perception and recovery.
Conclusion
Our results demonstrate that recovery from an episode of neck pain features a pattern
of significant improvements in pain coinciding with manual treatments, with small
relapses in pain scores between treatments. There is a relationship between immediate
improvements in pain during manual therapy treatment and speed of recovery, as well
as longer-term perceived benefits of treatment.Our findings also indicate that minor
adverse events or relapses during treatment are not associated with delayed recovery.
480
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482
Table 1.Baseline characteristics (n=181)
Age (years) 38.8 ±10.7

Sex-Female 117 (64.6%)
Current smoker 17 (9.4)
Neck pain duration (days) 19.5 ± 20.1
Neck-related disability (NDI) 15.5 ± 7.4
Past history of neck pain 114 (63.0%)
Past sick leave for neck pain 57 (31.5%)
Upper limb pain 144 (79.6%)
Upper back pain 115 (63.5%)
Lower back pain 71 (39.2%)
Headache 117 (64.6%)
Dizziness 56 (30.9%)
Nausea 41 (22.7%)
Data are Mean ± SD or N(%);NDI=Neck Disability Index (0-50)
483
Table 2.Differences between pain scores immediately reported to practitioner and
pain scores entered in participant diary the following day
Treatment Immediate post- Average 24-hour Mean difference

session treatment pain pain recorder by NRS between
recorded by patient the following practitioner and
practitioner. NRS day. NRS patient score.
Mean (SD) Mean (SD) (95%CI)
Treatment 1 4.2 (1.8) 5.4 (2.0) 1.2* (0.86 to 1.48)
Treatment 2 3.2 (1.8) 4.2 (2.2) 1.0* (0.70 to 1.31)
Treatment 3 2.5 (1.8) 3.2 (2.0) 0.7* (0.43 to 0.89)
Treatment 4 1.6 (1.6) 2.6 (2.1) 1.0* (0.71 to 1.26)
*p<0.1; NRS=Numerical rating scale (0-no pain, 10-worst possible pain)
484
8
Pain NRS (0-10) recorded by the
7
6.45
6
5 4.74
treating hh
4 4.2
3.89
3 3.18 3
2.53
2
1.64
1
0
Pre-Rx 1 Post-Rx 1 Pre-Rx 2 Post-Rx 2 Pre-Rx 3 Post-Rx 3 Pre-Rx 4 Post-Rx4
NRS = Numerical rating scale; Rx = treatment number
Figure 1. Clinical course of neck pain (Numerical Rating Score 0–10) during an
episode of manual therapy treatment demonstrating the “descending saw-tooth”
pattern of immediate improvement followed by slight relapse.
485

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Understanding Migraine

Maria Eliza Ruiz Aguila

A thesis submitted in fulfilment of the

requirements for the degree of

Faculty of Health Sciences

The University of Sydney

contains no material previously published or written by another person except where

supply a photocopy or microform of the thesis to an individual for research or study or to a

Maria Eliza Ruiz Aguila

Doctor of Philosophy (Health Sciences) is in a form ready for examination.

Faculty of Health Sciences

The University of Sydney

encouragement were critical in making my candidature fulfilling.I thank my co-authors for

insights taught me valuable lessons in collaborative research.

Australia, Australian Pain Society, Australian Pain Management Association, Painaustralia,

for ideas related to research and life.

strengthened my determination through the last four years.

neurochemical profile; cervical musculoskeletal impairments; and patient experience,

second, to compare levels of brain neurochemicals in migraine to controls; third, to explore

the relationship between brain neurochemicals and relevant disease characteristics of

migraine; fourth, to characterise cervical musculoskeletal impairments and patient experience

migraine and non-migraine headaches.

exploringand describingthe definitions of study populations in clinical trials of frequent

theeligibility criteria and baseline characteristics of participants. This review

Chapter Three, the levels of neurochemicals, particularly gamma-aminobutyric acid (GABA),

resonance spectroscopy (1H-MRS). Usingaspecialised technique called Mescher-Garwood

point resolved spectroscopy, two significantfindings were demonstrated. First, individuals

with migrainehad higher GABA levels[median (IQR)1.41 (1.31–1.50)institutional units]

compared to age- and gender-matched controls [1.18 (1.12–1.35)institutional units, p =

and suggest the potential of GABA as a biomarker for migraine.

pain, central sensitisation symptoms, emotional state, and headache-related disability, in

individuals with migraine were explored in a case-control design.Fair positive associations

associated with headache history, frequency, duration or intensity, with symptoms of

To characterise cervical musculoskeletal impairments and patient experience in different

Disability Questionnairethan the non-migraine group [27 (20–42); p = 0.006].Additionally, a

combination of the following variableshad 80.0% sensitivity and 75.6% specificity in

months in a longitudinal cohort design.The aim of this study was to characterisemigraine,

cervical musculoskeletal impairments, and other personal factors.Participants underwent

physical examination of cervical musculoskeletal impairments at baseline, completed an

volatility demonstrated in migraine. A multifactorial model comprising migraine headache

27.7% of the variation in disability at 3 months (p = 0.040). Likewise, a multifactorial model

cervical joint dysfunction, disability and physical activity.

The final objective of examining short- to medium-term changes in disability in different

headachetypes was investigated inChapter Seven.The internal responsiveness of four

commonlyused questionnaires was evaluated by calculating effect size, and external

responsiveness was calculated using receiver operating characteristic curve analysis.The

to 0.94). Headache Disability Questionnaire generally had the greatest external

usefulquestionnaires to use in clinical practice.

Collectively, this thesis provides deeperinformation regardingthe nature and characteristics of

targeted at GABA or at the clinical characteristics found to be present in migraine. Ultimately

Candidate’s statement ............................................................................................................ i

Acknowledgements .............................................................................................................. iii

Table of contents .................................................................................................................. xi

Thesis structure ................................................................................................................. xvii

Publications, presentations and prizes ............................................................................... xviii

CHAPTER ONE Current understanding of migraine and recurrent non-migraine neck-

related headaches ................................................................................................................ 1

Headache definition, classification and diagnosis ............................................................ 4

The prevalence of migraine and non-migraine headaches .............................................. 11

The burden of migraine and non-migraine headaches .................................................... 12